Ingestible pill for diagnosing a gastrointestinal tract

ABSTRACT

An ingestible device, adapted to travel in the gastrointestinal tract and perform a diagnostic image of tissue therein, is provided. The diagnostic image may comprise diagnostic information as a function of time, or diagnostic information as a function of distance traveled within the gastrointestinal tract. An imaging method by depth calculations is provided, based on the attenuation of photons of different energies, which are emitted from the same source, coupled with position monitoring.

This is a continuation-in-part of U.S. patent application Ser. No.10/240,239, filed on Sep. 30, 2002, which is a National Phaseapplication of PCT/IL02/00057, filed on Jan. 22, 2002, which is acontinuation-in-part U.S. patent application Ser. No. 09/765,316 filedJan. 22, 2001, now abandoned which derived priority form U.S.Provisional Application No. 60/285,233, filed on Apr. 23, 2001Additionally, this application is filed concurrently with co-pendingapplication Ser. No. 10/616,307 “RADIOACTIVE EMISSION DETECTOR EQUIPPEDWITH A POSITION TRACKING SYSTEM,” whose disclosure is incorporatedherein by reference, and both applications derive priority from U.S.Provisional application No. 60/394,936, filed on Jul. 11, 2002.

BACKGROUND AND FIELD OF THE INVENTION

The present invention relates generally to the field of the diagnosis ofailments of said gastrointestinal tract, and particularly, to aningestible device that travels in the gastrointestinal tract andperforms diagnosis therein.

The impact of cancer of the gastrointestinal tract is grave. In spite ofenormous expenditures of financial and human resources, early detectionof malignant tumors remains an unfulfilled medical goal. While it isknown that a number of cancers are treatable if detected at an earlystage, lack of reliable screening procedures results in their beingundetected and untreated.

There are other gastrointestinal-tract disorders, which similarlyrequire reliable screening and diagnostic procedures for early detectionand treatment. These include, for example, irritable bowel syndrome,fluxional diarrhea, ulcerative colitis, collagenous colitis, microscopiccolitis, lymphocytic colitis, inflammatory bowel disease, Crohn'sdisease, infectious diarrhea, ulcerative bowel disease, lactasedeficiency, infectious diarrhea, amebiasis, and giardiasis.

To some extent, simple diagnostic procedures for gastrointestinalpathologies may be employed, as part of routine checkups. For example,sampling for blood in the stool is a screening technique for digestivetract cancer. However, this procedure is not very sensitive, becauseblood is released when comparatively large polyps develop. Sometimes,there is no release of blood to the stool until very late in thedevelopment of the disease.

Additionally, PCT International Application WO92/00402 PCT describes anon-invasive method for detecting gastric epithelial damage using adisaccharide such as sucrose, maltose or lactose which is orallyadministered to a patient. Blood and urine samples are then assayed, forthe disaccharide, to determine the existence and extent of gastricepithelial damage. However, this method does not reliably detect damageof the intestinal tract.

For more reliable diagnoses, various forms of endoscopes and otherimaging apparatus may be used.

Diagnosis of different conditions of the colon generally involves usinga colonoscope. A typical colonoscope includes, at its distal end, withrespect to an operator, a light source, a video chip, and a suctionchannel. These elements are all in communication with a proximal end ofthe colonoscope via wires and channels housed within a flexible tube.The distal end is inserted into a patient's rectum and can be maneuveredalong the length of the colon. A colonoscope can be inserted far enoughinto a patient's colon for the distal end to enter the patient's cecum.The tip of the colonoscope can also be maneuvered through the ileo-cecalvalve into the terminal ileum.

A colonoscope provides a visual image only of the region of the colonthat is immediately near the light source and video chip, yieldingvisual information for only a small region of the colon at any giventime. Lesions in a patient's colon typically are identified byprogressive and painstaking visual examination of the entire colon.However, a single colonoscopy is often not sufficient to identify thesource of colorectal bleeding which is typically sporadic and in manycases would be best located by observing the entire colon over a periodof time.

Various attachments to a colonoscope allow small surgical procedures,such as tissue biopsies, to be carried out during a colonoscopicexamination.

Endoscopy of the small intestine is also known. U.S. Pat. No. 5,984,860,to Shan, entitled, “Pass-through duodenal enteroscopic device,” whosedisclosure is incorporated herein by reference, describes a tetheredingestible, enteroscopic video camera, which utilizes the naturalcontraction wave of the small intestine to propel it through the smallintestine at about the same speed as any other object therein. The videocamera includes an illumination source at its forward end. Covering thecamera lens and illumination source is a transparent inflatable balloon,adapted to gently expand the small intestine immediately forward thecamera for better viewing. A small diameter communication and powercable unwinds through an aperture in the rear of the camera as it movesthrough the small intestine. Upon completion of movement through thesmall intestine the cable is automatically separated, permitting thecable to be withdrawn through the stomach and intestine. The cameracontinues through the large intestine and passes from the patientthrough the rectum.

The aforementioned endoscopes, while providing means to access andvisualize portions of the gastrointestinal track, do not provide meansof detecting gastrointestinal pathologies, which are not clearlyvisible. In particular, they do not provide means for localization anddifferentiation of occult tumors. Typically, a large tumor is readilylocated by visualization. Yet, for subsequent operative success, as wellas for the success of other forms of treatment, it is necessary tosomehow locate tumors in their occult stage, when they cannot be foundby sight and feel.

The use of radiolabeled immunoglobulin for tumor localization was shownto be possible in 1959 when Day et al. radiolabeled isolated antifibrin.(Day, E. O.; Planisek, J. A.; Pressman D: “Localization ofRadioiodinated Rat Fibrinogen in Transplanted Rat Tumors”, J. Natl.Cancer Inst. 23: 799-812, 1959). Fibrin, while not a tumor-specificantigen, was known to have a frequency of presence in tumors due to theinflammatory process-accompanying invasion. Day et al. demonstrated thata protein in high concentration in tumor sites could be used to localizetumors. The antibodies against human fibrin and ferritin were used inattempts to employ specific immunoglobulins for diagnosis.

Since the work of Day et al, in 1959, an expanding number of monoclonalantibodies have received FDA approval. Examples, applicable togastrointestinal tract tumors, include the following:

-   1. CEA-Scan is a Tc^(99m)-labeled monoclonal antibody fragment,    which targets CEA—produced and shed by colorectal carcinoma cells.    The use of anti-CEA monoclonal antibody has been recommended as the    only marker to estimate prognosis and response to therapy. Anti-CEA    monoclonal antibody may also be labeled by other radioisotopes, for    example, iodine isotopes. (Jessup J M. 1998, Tumor    markers—prognostic and therapeutic implications for colorectal    carcinoma, Surgical Oncology; 7: 139-151.)-   2. In¹¹¹-Satumomab Pendetide (Oncoscint®) is designed to target    TAG-72. TAG-72 is a mucin-like glycoprotein expressed in human    colorectal, gastric, ovarian, breast and lung cancers. It is rarely    expressed in normal human adult tissues. (Molinolo A; Simpson J F;    et al. 1990, Enhanced tumor binding using immunohistochemical    analyses by second generation anti-tumor-associated glycoprotein 72    monoclonal antibodies versus monoclonal antibody B72.3 in human    tissue, Cancer Res. 50(4): 1291-8.)-   3. Lipid-Associated Sialic Acid (LASA) is a tumor antigen, which for    colorectal carcinoma LASA, has a similar sensitivity as CEA but a    greater specificity for differentiating between benign and malignant    lesions. (Ebril K M, Jones J D, Klee G G. 1985, Use and limitations    of serum total and lipid-bound sialic acid concentrations as markers    for colorectal cancer, Cancer; 55:404-409.)-   4. Matrix Metaloproteinase-7 (MMP-7) is a proteins enzyme, believed    to be involved in tumor invasion and metastasis. Its expression is    elevated in tumor tissue compared to normal tissue and may be a    potential marker for tumor aggressiveness and traditional staging.    (Mori M, Barnard G F et al. 1995, Overexpression of matrix    metalloproteinase-7 mRNA in human colon carcinoma Cancer; 75:    1516-1519.)

Additionally, pharmaceuticals may be used as markers for nonmalignantpathologies, such as gastrointestinal inflammations and infections.Examples include the following:

-   1. Ga⁶⁷ citrate binds to transferrin and is used for detection of    chronic inflammation. (Mettler F A, and Guiberteau M J, Eds. 1998,    Inflammation and infection imaging. Essentials of nuclear medicine.    Fourth edition. Pgs: 387-403.)-   2. Nonspecific-polyclonal immunoglobulin G (IgG) may be labeled with    both In¹¹¹ or Tc^(99m), and has a potential to localize nonbacterial    infections. (Mettler F A, and Guiberteau M J, ibid.)-   3. Radio-labeled leukocytes, such as such as In¹¹¹ oxine leukocytes    and Tc^(99m) HMPAO leukocytes are attracted to sites of    inflammation, where they are activated by local chemotactic factors    and pass through the endothelium into the soft tissue. Labeled    leukocytes in the gastrointestinal tract are nonspecific and may    indicate a number of pathologies, including Crohn's disease,    ulcerative colitis, psudomembranous colitis, diverticulosis, various    gastrointestinal infections, fistulas, ischemic or infracted bowel.    (Mettler F A, and Guiberteau M J, ibid; Corstens F H; van der Meer    J W. 1999. Nuclear medicine's role in infection and inflammation.    Lancet; 354 (9180): 765-70.)

The particular choice of a radionuclide for labeling antibodies isdependent upon its nuclear properties, the physical half-life, thedetection instruments' capabilities, the pharmacokinetics of theradiolabeled antibody, and the degree of difficulty of the labelingprocedure. Examples of radionuclides used for labeling antibodiesinclude Technetium Tc^(99m), Iodine I¹²⁵, I¹²³, I¹³¹, and I¹³³, IndiumIn¹¹¹, Gallium Ga⁶⁷, thallium Tl²⁰¹, fluorine F¹⁸ and P³².

Nuclear-radiation imaging of radionuclide-labeled antibodies is asubject of continued development and study. A particular difficulty inusing radionuclides is that blood-pool background radioactivity hascaused ordinary scintigrams to prove difficult to interpret. Computersubtraction of radioactive blood-pool background radioactivity has beenattempted to enhance imaging. Yet the ability to detect occult tumorshas remained low.

An attempt to overcome the blood-pool background radioactivity isdescribed in U.S. Pat. No. 4,782,840 to Martin, Jr., et al., entitled,“Method for locating, differentiating, and removing neoplasms,” whosedisclosure is incorporated herein by reference. Martin, Jr., et aldescribe a method for improved localization, differentiation and removalof neoplastic tissue in animals. The improved method commences with theadministering to the animal of an effective amount of a labeled antibodyspecific for neoplastic tissue and labeled with a radioactive isotopeexhibiting specific photon emissions of energy levels. A waiting periodfollows, to permit the labeled antibody to preferentially concentrate inany neoplastic tissue present in the animal and to allow blood-poolbackground radioactivity to decrease, thus increasing the ratio ofphoton emissions from neoplastic tissue to background photon emissionsin the animal. Thereafter, a general background photon-emission count isdetermined, for the tissue. Once the background count has beendetermined, the tissue suspected of being neoplastic is accessed bysurgical means, and a handheld probe is manually maneuvered along thattissue. The probe is configured for fascicle hand positioning andmaneuvering. The probe is characterized by a collimatable radiationdetector having a selective photon entrance and having an outputderiving discrete signals responsive to photon emissions when theentrance is positioned immediately adjacent thereto. The probe furthercomprises amplifier means having an input coupled with the radiationdetector output and responsive to the discrete signals to providecorresponding amplified output pulses. Finally, the probe comprisesreadout means responsive to the output pulses and actuable to an initialcondition for commencing the provision of a perceptible indication of anindicia corresponding to the number of the output pulses received. Fromthe perceptible indication, the extent of tissue exhibiting a number ofoutput pulses having a value above background output pulses isdetermined and such tissue is removed surgically.

Due to the proximity of the detection probe to the labeled antibody, thefaint radiation emanating from occult sites becomes detectable. This isin part because of the inherent application of the approximate inversesquare law of radiation propagation, and in part because thecollimatable radiation detector may be maneuvered at various angles withrespect to the suspected neoplastic tissue, so that at some positions,the collimator is aligned with the source of radiation. The procedurenow is known as radioimmunoguided surgery, or RIGS™. (RIGS is aregistered trademark of Neoprobe Corporation of Dublin, Ohio).

The RIGS™ system for surgery is successful because the blood-poolbackground of the circulating radiolabeled antibody is cleared from thebody prior to imaging with the probe. As a consequence, the photonemissions or radiation emitted at minute tumors, compared to surroundingtissue, become detectable. Fortuitously, the radiolabeled antibody iscapable of remaining bound to or associated with neoplastic tissue forextended periods of time with the radio tag still bound thereto. Eventhough the accretion of radioactivity at the tumor site decreases overtime, the blood-pool background at surrounding tissue (relative to thetumor sites) decreases at a much greater rate.

RIG instrumentation generally includes two basic components, a hand-heldprobe, as described hereinabove, and a control console, in electricalcommunication with hand-held probe, via a flexible cable. The controlconsole is located within the operating room facility but out of thesterile field, while the hand-held probe and forward portions of itsassociated cable are located within that field. The hand-heldradiation-detecting probe is relatively small and performs inconjunction with a cadmium-zinc-telluride detector or crystal.

Further work continued to improve the sensitivity of RIGS™ to the minutenumber of photons that may be emitted from an occult tumor. U.S. Pat.No. 4,801,803 to Denen, et al., entitled, “Detector and localizer forlow energy radiation emissions,” whose disclosure is incorporated hereinby reference, describes a probe particularly suited for use inimmuno-guided surgery capable of detecting very faint gamma emissionsand thereby localizing cancerous tumor. Detection is achieved under roomtemperature conditions using a crystal such as cadmium telluride. Toachieve the extreme sensitivity capabilities of the apparatus, aninstrumentation approach has been developed in which the somewhatfragile crystal is securely retained in isolation from externallyinduced incidents otherwise creating excessive noise. Microphoniceffects are minimized through employment of a sequence of materialsexhibiting divergent acoustic impedance. Capacitive effects caused byminute intercomponent movements are controlled to acceptable levels.

Additionally, a preamplifier is incorporated within the probe itself,which employs an integrator stage front end combining a field effecttransistor and bipolar device with a very small feedback capacitance ofless than one picofarad. A bootstrap technique is utilized to enhancethe amplification of the bipolar amplification stage. Pulse relatedsignals outputted from the device are normalized and compared to producepulse data, which are analyzed. In one mode of operation a siren effectis employed to guide the surgeon towards emission sources.

The aforementioned probe is directed at low energy radionuclides, suchas I¹²⁵. Additionally, the distribution of radiolabeled antibody withthe nuclide is quite sparse so that background emissions can beminimized and the ratio of tumor-specific counts received to backgroundcounts can be maximized. The probe instrument and related controlcircuitry has been assigned the trade designation “NEOPROBE” instrument.

Further improvements to the “NEOPROBE” instrument are described in U.S.Pat. No. 5,151,598 to Denen, entitled, “Detector and localizer for lowenergy radiation emissions,” whose disclosure is incorporated herein byreference. Further improvements include controlling capacitive andpiezoelectric effects occasioned by the most minute of intercomponentmovements. Additionally, compressive retention of the crystal andelectrical contacts is employed in conjunction with electricallyconductive but pliable surface supports.

Additionally, improvements to the “NEOPROBE” instrument are described inU.S. Pat. No. 4,893,013 to Denen et al., entitled, “Detector andLocalizer for Low Energy Radiation Emissions,” and U.S. Pat. No.5,070,878 to Denen, entitled, “Detector and localizer for low energyradiation emissions,” whose disclosures are incorporated herein byreference. The probe includes a cadmium telluride crystal, secured in alight-tight environment. A noise immune structuring of the probe andcrystal combination includes the utilization of electrically conductive,compliant cushion layer located at one face of the crystal inconjunction with freely abutting biasing and ground contacts. A nylon,resilient retainer is positioned in tension over the assemblage ofcrystal, ground and biasing contacts and compliant layers to achieve acompressively retained assemblage. A dead air space is developed betweenthe forward facing window of the probe and the crystal retainingassemblage.

To derive data representing the presence or absence of occult tumor, amicroprocessor-driven complex system of analysis continuously works tostatistically evaluate validated counts or gamma strikes to apprise thesurgeon of the presence or absence of occult neoplastic tissue. U.S.Pat. No. 4,889,991 by Ramsey and Thurston, entitled, “Gamma RadiationDetector with Enhanced Signal Treatment,” whose disclosure isincorporated herein by reference, describes an algorithm under whichsuch an evaluation takes place. Accordingly, a hand-held gamma radiationprobe, such as NEOPROBE instrument, is employed, in conjunction with acontrol function which provides an enhanced audio output, directed forcueing the user to the source position, as he maneuvers the probe alongthe tissue. The probe is positioned at a location on the animal bodyrepresenting background radiation and a squelch low count rate isdeveloped therefrom. The squelch low count rate is multiplied by a rangefactor to develop a squelch high-count rate and frequencies aredeveloped from a look-up frequency table from lowest to highest incorrespondence with the developed high and low squelch count rates. Slewrate limiting of the count rates is provided by development of a squelchdelta value representing the difference between the squelch high and lowcount rates divided by a time element. Selection of frequencies foraudio output from the frequency table is limited by the value of thesquelch delta value. Weighting of received radiation counts is carriedout continuously to develop count rate values used by the system.

U.S. Pat. No. 6,259,095, to Boutun, et al., entitled, “System andapparatus for detecting and locating sources of radiation,” whosedisclosure is incorporated herein by reference, describes furtherimprovements to the aforementioned probes of Neoprobe Corporation. Theapparatus incorporates a large window display utilizing icon imagery toidentify counting functions such as target count and background. Avariety of radionuclide modes of operation can be selected by theoperator and the system automatically defaults to detector biasselection and window reference voltage selection in correspondence withthe elected radionuclide. A bar graph readout apprises the user of theamount of time or count level remaining in a target or backgroundprocedure and the flashing of icon identifiers occurs during suchprocedures. Pulse validation is improved by the utilization of adiscriminator, which evaluates pulse width.

In spite of these advances, background radiation remains an obstaclethat limits the probe sensitivity to occult tumors, and there arecontinued endeavors to minimize its effect.

Optical fluorescence spectroscopy is a known imaging technique.

When a sample of large molecules is irradiated, for example, by laserlight, it will absorb radiation, and various levels will be excited.Some of the excited states will return back substantially to theprevious state, by elastic scattering, and some energy will be lost ininternal conversion, collisions and other loss mechanisms. However, someexcited states will create fluorescent radiation, which, due to thedistribution of states will give a characteristic wavelengthdistribution.

Some tumor-marking agents give well-structured fluorescence spectra,when irradiated by laser light. In particular, hematoporphyrinderivatives (HPD), give a well-structured fluorescence spectrum, whenexcited in the Soret band around 405 nm. The fluorescence spectrum showstypical peaks at about 630 and 690 nm, superimposed in practice on moreunstructured tissue autofluorescence. Other useful tumor-marking agentsare dihematoporphyrin ether/ester (DHE), hematoporphyrin (HP),polyhematoporphyrin ester (PHE), and tetrasulfonated phthalocyanine(TSPC), when irradiated at 337 nm (N₂ laser)

U.S. Pat. No. 5,115,137, to Andersson-Engels, et al, entitled,“Diagnosis by means of fluorescent light emission from tissue,” whosedisclosure is incorporated herein by reference, relates to improveddetection of properties of tissue by means of induced fluorescence oflarge molecules. The tissue character may then be evaluated from theobserved large-molecule spectra According to U.S. Pat. No. 5,115,137,the spectrum for tonsil cancer is clearly different from normal mucosa,due to endogenous porphyrins.

Similarly, U.S. Pat. No. 4,785,806, to Deckelbaum, entitled, “Laserablation process and apparatus,” whose disclosure is incorporated hereinby reference, describes a process and apparatus for ablatingatherosclerotic or neoplastic tissues. Optical fibers direct low powerlight energy at a section of tissue to be ablated to cause the sectionto fluoresce. The fluorescence pattern is analyzed to determine whetherthe fluorescence frequency spectrum is representative of normal orabnormal tissue. A source of high power, ultraviolet, laser energydirected through an optical fiber at the section of tissue is fired onlywhen the fluorometric analysis indicates that it is directed at abnormaltissue.

Additionally, U.S. Pat. No. 4,682,594, to Mok, entitled, “Probe-and firelasers,” whose disclosure is incorporated herein by reference, describesa method and apparatus of irradiating a treatment area within a body,such as blood vessel plaque. The method includes initially administeringto the patient a non-toxic atheroma-enhancing reagent which causes theplaque to have a characteristic optical property when illuminated with agiven radiation, introducing a catheter system including fiberopticcable means into the artery such that the distal end thereof isoperatively opposite the plaque site, introducing into the proximal endof the fiberoptic cable means the given radiation, photoelectricallysensing at the proximal end the characteristic optical property togenerate a control signal, and directly under the control of the controlsignal transmitting via the cable means from the proximal end to thedistal end, periodically occurring laser pulses until the characteristicoptical property is no longer sensed.

A related fluorescence technique is described in U.S. Pat. No. 4,336,809to Clark, entitled. “Human and animal tissue photoradiation system andmethod,” whose disclosure is incorporated herein by reference. Itrelates to utilizing certain dyes, which not only selectively stainneoplastic tissue but also fluoresce in response to irradiation.Additionally, they are photodynamically cytotoxic in response to aproper wavelength of light in the presence of oxygen within livingtissue. One of the dyes that is presently preferred for thesecharacteristics contains hematoporphyrin or hematoporphyrin derivativesthat when administered intravenously remain at higher concentrations forlonger periods of time in traumatized or malignant tumorous tissue thanin normal tissue. This dye also has a strong absorption peak centered ata wavelength of approximately 407 nanometers and responds to excitationat about this wavelength by fluorescing at a wavelength of about 614nanometers. This makes tumor diagnosis possible by injecting the dye,allowing it to concentrate in tumorous tissue, irradiating the tissuewith deep blue violet light, and observing red fluorescence. Thus, thedifference in the optical property of the stained tissue and theunstained healthy tissue improves the visualization of the treatmentarea. This same dye has a photodynamic absorption peak at a wavelengthof about 631 nanometers and is cytotoxic to malignant tissue containingthe dye when irradiated with red light of about this wavelength. Fordiagnostic purposes krypton ion laser was used for its 406.7/413.1nanometer lines matching the 407 nanometer absorption peak ofhematoporphyrin.

U.S. Pat. No. 6,258,576, to Richards-Kortum, et al., entitled,“Diagnostic method and apparatus for cervical squamous intraepitheliallesions in vitro and in vivo using fluorescence spectroscopy,” whosedisclosure is incorporated herein by reference, relates to the use ofmultiple illumination wavelengths in fluorescence spectroscopy for thediagnosis of cervical cancer and precancer. In this manner, it has beenpossible to (i) differentiate normal or inflamed tissue from squamousintraepithelial lesions (SILs) and (ii) differentiate high grade SILsfrom non-high grade SILs. The detection may be performed in vitro or invivo. Multivariate statistical analysis has been employed to reduce thenumber of fluorescence excitation-emission wavelength pairs needed tore-develop algorithms that demonstrate a minimum decrease inclassification accuracy.

For example, the method of the aforementioned patent may compriseilluminating a tissue sample with electromagnetic radiation wavelengthsof about 337 nm, 380 nm and 460 nm, to produce fluorescence; detecting aplurality of discrete emission wavelengths from the fluorescence; andcalculating from the emission wavelengths a probability that the tissuesample belongs in particular tissue classification.

Ultrasound is another known imaging technique. Conventional ultrasonicprobes are used for internal examinations in the field of obstetrics,gynecology, urology and the like.

U.S. Patent Application 20010020131, to Kawagishi, Tetsuya, et al.,entitled, “Ultrasonic diagnosis system,” whose disclosure isincorporated herein by reference, describes an ultrasonic diagnosisapparatus that has an ultrasonic probe, having a plurality of arrayedtransducer elements, a transmitting beam former for generating drivingsignals for driving transducer elements, and a receiving beam former forgenerating receiving signals based on echo signals received bytransducer elements. The transmitting beam former generates drivingsignals so that phases of ultrasonic waves generated from transducerelements are aligned at multiple focal points. An image processorextracts harmonic components from receiving signals of ultrasonic waveshaving multiple focal points, and generates ultrasonic image data basedon the harmonic components.

U.S. Pat. No. 5,088,500 to Wedel., et al., entitled, “Ultrasound fingerprobe and method for use,” whose disclosure is incorporated herein byreference, describes a method and apparatus for performing ultrasoundrectal examinations, by providing an ultrasound transducer which isslipped over the physician's finger tip and then inserted into thepatient's rectum, together with an apparatus for guiding medicalinstruments into the area to be imaged.

Similarly, U.S. Pat. No. 5,284,147, to Hanoaka, et al., entitled,“Ultrasonic probe to be installed on fingertip,” whose disclosure isincorporated herein by reference, relates to an ultrasonic probe to beinserted into the body of a subject for image-processing a diagnostictarget thereof by ultrasonic waves transmitted to and received from theinside of the body. More particularly, it relates to an internalexamination ultrasonic probe which can be directly installed on apalpation finger. The ultrasonic probe includes a transducer array fortransmitting and receiving the ultrasonic waves; a housing forsupporting the transducer array, which housing is provided with a devicefor installing a fingertip of an operator therein; and electric wiringmembers connected to the transducer array and extending from the housingto the outside so that transmission and reception signals of theultrasonic waves are supplied therethrough.

Contrast agents may be used in conjunction with ultrasound imaging, forexample as taught by U.S. Pat. No. 6,280,704, to Schutt, et al.,entitled, “Ultrasonic imaging system utilizing a long-persistencecontrast agent,” whose disclosure is incorporated herein by reference.

Temperature imaging for locating and detecting neoplastic tissue is alsoknown. In the 1950's, it was discovered that the surface temperature ofskin in the area of a malignant tumor exhibited a higher temperaturethan that expected of healthy tissue. Thus, by measuring body skintemperatures, it became possible to screen for the existence of abnormalbody activity such as cancerous tumor growth. With the development ofliquid crystals and methods of forming temperature responsive chemicalsubstrates, contact thermometry became a reality along with its use inmedical applications. Devices employing contact thermometry could senseand display temperature changes through indicators which changed colors,either permanently or temporarily, when placed in direct physicalcontact with a surface such as skin, reflecting a temperature at or nearthe point of contact. An abnormal reading would alert a user to the needfor closer, more detailed examination of the region in question.However, the art in this area has been directed primarily at sensing anddisplaying temperatures on exterior skin surfaces. Thus, for example,the patent to Vanzetti et al. (U.S. Pat. No. 3,830,224) disclosed theplacement of temperature responsive, color changing liquid crystals atvarious points in a brassiere for the purpose of detecting the existenceof breast cancer, while the patent to Sagi (U.S. Re. No. 32,000)disclosed the use of radially arranged rows of temperature responsiveindicators deposited on a disc for insertion into the breast-receivingcups of a brassiere for the same purpose.

Additionally, Tomatis, A., et al, studied reflectance images of 43pigmented lesions of the skin (18 melanomas, 17 common melanocytic naeviand eight dysplastic naevi). Reflectance images were acquired by atelespectrophotometric system and were analyzed in the spectral rangefrom 420 to 1040 nm, to discriminate melanoma from benign melanocyticentities. Different evaluations were carried out considering the wholespectrum, the visible and the near infrared. A total of 33 (76.7%)lesions were correctly diagnosed by the telespectrophotometric system,compared with 35 (81.4%) correct clinical diagnoses. Reflectance in theinfrared band appears diagnostically relevant.

It is believed that the same principle may apply to internal bodyorgans. An abnormally high temperature at the surface of an internalorgan when compared with surrounding tissue may also indicate thelikelihood of a medical problem. Thus, there are advantages todiagnostic measurements of temperature in body cavities for earlyindications of abnormalities. These may provide simple, speedy, accurateand cost-effective solution to screening procedures.

U.S. Pat. No. 6,135,968, to Brounstein, entitled, entitled,“Differential temperature measuring device and method,” whose disclosureis incorporated herein by reference, describes a device and method forsensing temperatures at internal body locations non-surgicallyaccessible only through body orifices. The device is particularly usefulin medical applications such as screening for cancer and other abnormalbiological activity signaled by an increase in temperature at a selectedsite. As applied to prostate examinations, the device is temporarily,adhesively affixed to a user's fingertip or to a mechanical probe. Inthe preferred embodiment, the device includes two temperature-sensingelements, which may include a plurality of chemical indicators. Eachindicator changes color in response to detection of a predeterminedparticular temperature. When properly aligned and installed, the firstelement is located on the palmar surface of the fingertip while thesecond element is located on the dorsal surface of the fingertip. Afteran examination glove has been donned over the fingertip carrying thedevice, a prostate examination is performed during which the firstelement is brought into constant but brief contact with the prostateregion and the second element is similarly, simultaneously brought intocontact with a dermal surface opposing the prostate region. Uponwithdrawal of the fingertip from the rectum and removal of the glove,the two temperature sensing elements may be visually examined in orderto determine the temperatures detected by each one. A significantdifference in observed temperatures indicates the possibility ofabnormal biological activity and the need for further diagnostic ormedical procedures.

Infrared thermography is a temperature imaging technique, which measuresthermal energy emitted from the body surface without contact, quicklyand dynamically, and produces a temperature image for analysis.Harzbecker K, et al. report, based on thermic observations in 63patients and a control experiment in 15 persons, on experiences withthermography in the diagnosis of diseases, which are localized moreprofoundly in the thoracic cavity. (Harzbeeker K, et al., “Thermographicthorax diagnostics,” Z Gesamte Inn Med. Feb. 1, 1978; 33(3):78-80.)

Similarly, Dexter L I, Kondrat'ev V B. report data concerning the use oflymphography and thermography for the purpose of establishing adifferential diagnosis in 42 patients with edema of the lower limbs of adifferent origin. A comparative estimation of different methods of thedifferential diagnosis indicated the advantages of infraredthermography. (Dexter L I, Kondrat'ev V B., “Thermography indifferential diagnosis of lymphostasis in the lower limbs,” Vestn KhirIm I I Grek. 1976 June; 116(6):60-4.)

Electrical Impedance imaging is another known imaging technique fordetecting tumors. Relying on inexpensive probes, it provides a simplescreening procedure, particularly for breast cancer. (“Breast Cancerscreening by impedance measurements” by G. Piperno et al. Frontiers Med.Biol. Eng., Vol. 2, pp 111-117). It involves systems in which theimpedance between a point on the surface of the skin and some referencepoint on the body of a patient is determined. Sometimes, a multi-elementprobe, formed as a sheet with an array of electrical contacts is used,for obtaining a two-dimensional impedance map of the tissue, forexample, the breast. The two-dimensional impedance map may be used,possibly in conjunction with other data, such as mammography, for thedetection of cancer.

Rajshekhar, V., describes using an impedance probe having a singleelectrode to measure the impedance characteristics of lesions(“Continuous impedance monitoring during CT-guided stereotactic surgery:relative value in cystic and solid lesions,” Rajshekhar, V., BritishJournal of Neurosurgery, 1992, 6, 439-444). The objective of the studywas to use the measurements made in the lesions to determine the extentof the lesions and to localize the lesions more accurately. The probe isguided to the tumor by CT and four measurements were made within thelesion as the probe passed through the lesion. A biopsy of the lesionwas performed using the outer sheath of the probe as a guide toposition, after the probe itself was withdrawn.

U.S. Pat. No. 4,458,694, to Sollish, et al., entitled, “Apparatus andmethod for detection of tumors in tissue,” whose disclosure isincorporated herein by reference, relates to apparatus for detectingtumors in human breast, based on the dielectric constants of localizedregions of the breast tissue. The apparatus includes a probe, comprisinga plurality of elements. The apparatus further includes means forapplying an AC signal to the tissue, means for sensing electricalproperties at each of the probe elements at different times, and signalprocessing circuitry, coupled to the sensing means, for comparing theelectrical properties sensed at the different times. The apparatus thusprovides an output of the dielectric constants of localized regions ofbreast tissue associated with the probe.

Similarly, U.S. Pat. No. 4,291,708 to Frei, et al., entitled, “Apparatusand method for detection of tumors in tissue,” whose disclosure isincorporated herein by reference, relates to apparatus for detectingtumors in human breast tissue. The apparatus includes means fordetermining the dielectric constants of a plurality of localized regionsof human breast tissue. These include a bridge, which is provided with acircuit for automatically nulling the bridge while in operation. Meansare further provided for measuring variations in the dielectricconstants over a plurality of the regions and for indicating thepossible presence of a tumor as result of the measurement. The apparatusmay be utilized in carrying out a method of detecting tumors whichincludes the steps of applying a plurality of probe elements to breasttissue for sensing characteristics of localized regions thereof,applying an electrical signal to the probe elements for determiningdielectric constants of localized regions of the tissue, sensingvariations in the dielectric constants and determining therate-of-change of dielectric constant at each of the localized regions.

U.S. Pat. Nos. 6,308,097, 6,055,452 and 5,810,742, to Pearlman, A. L.,entitled, “Tissue characterization based on impedance images and onimpedance measurements,” whose disclosures are incorporated herein byreference, describe apparatus for aiding in the identification of tissuetype for an anomalous tissue in an impedance image comprising: means forproviding an polychromic immitance map of a portion of the body; meansfor determining a plurality of polychromic measures from one or both ofa portion of the body; and a display which displays an indication basedon said plurality of polychromic measures.

Magnetic resonance imaging (MRI) is based on the absorption and emissionof energy in the radio frequency range of the electromagnetic spectrum,by nuclei having unpaired spins.

The hardware components associated with an MRI imager are:

-   i. a primary magnet, which produces the B_(o) field for the imaging    procedure;-   ii. gradient coils for producing a gradient in B_(o);-   iii. an RF coil, for producing the B_(I) magnetic field, necessary    to rotate the spins by 90° or 180° and for detecting the NRI signal;    and-   iv. a computer, for controlling the components of the MRI imager.

Generally, the magnet is a large horizontal bore superconducting magnet,which provides a homogeneous magnetic field in an internal region withinthe magnet. A patient or object to be imaged is usually positioned inthe homogeneous field region located in the central air gap for imaging.

A typical gradient coil system comprises an antihelmholtz type of coil.These are two parallel ring shaped coils, around the z axis. Current ineach of the two coils flows in opposite directions creating a magneticfield gradient between the two coils.

The RF coil creates a B₁ field, which rotates the net magnetization in apulse sequence. They may be: 1) transmit and receive coils, 2) receiveonly coils, and 3) transmit only coils.

In this geometry, use of catheters equipped with miniature RF coils forinternal imaging of body cavities, still requires positioning thepatient in a conventional large MRI magnet. This environment can resultin deficient images because the various orientations of the RF coil,e.g., in an artery, will not be positioned always colinearly with the RFexcitation field.

This problem has been resolved by U.S. Pat. No. 5,572,132, to Pulyer, etal., entitled, “MRI probe for external imaging,” whose disclosure isincorporated herein by reference, wherein an MRI catheter forendoscopical imaging of tissue of the artery wall, rectum, urinal tract,intestine, esophagus, nasal passages, vagina and other biomedicalapplications is described.

The invention teaches an MRI spectroscopic probe having an externalbackground magnetic field B₀ (as opposed to the internal backgroundmagnetic filed of the large horizontal bore superconducting magnet.) Theprobe comprises (i) a miniature primary magnet having a longitudinalaxis and an external surface extending in the axial direction and (ii) aRF coil surrounding and proximal to said surface. The primary magnet isstructured and configured to provide a symmetrical, preferablycylindrically shaped, homogeneous field region external to the surfaceof the magnet. The RF coil receives NMR signals from excited nuclei. Forimaging, one or more gradient coils are provided to spatially encode thenuclear spins of nuclei excited by an RF coil, which may be the samecoil used for receiving NMR signals or another RF coil.

U.S. Pat. No. 6,315,981 to Unger, entitled, “Gas filled microspheres asmagnetic resonance imaging contrast agents,” whose disclosure isincorporated herein by reference, describes the use of gas filledmicrospheres as contrast agents for magnetic resonance imaging (MRI).Unger further describes how gas can be used in combination with polymercompositions and possibly also with paramagnetic, superparamagnetic, andliquid fluorocarbon compounds as MRI contrast agents. It is furthershown how the gas stabilized by polymers would function as an effectivesusceptibility contrast agent to decrease signal intensity on T2weighted images; and that such systems are particularly effective foruse as gastrointestinal MRI contrast media.

Ingestible radio pills, which are ingestible capsules containing atransmitter are known. In 1964 research at Heidelberg Universitydeveloped a pill for monitoring pH of the gastrointestinal tract.(Noller, H. G., “The Heidelberg Capsule Used For the Diagnosis of PepicDiseases”, Aerospace Medicine, February 1964, pp. 15-117.)

U.S. Pat. No. 4,844,076, to Lesho, et al., of July 1989, entitled,“Ingestible size continuously transmitting temperature monitoring pill,”whose disclosure is incorporated herein by reference, describes atemperature responsive transmitter, encapsulation in an ingestible sizecapsule. The capsule is configured to monitor average body temperature,internally. The ingestible size temperature pill can be configured in arechargeable embodiment. In this embodiment the pill uses the inductivecoil in the tank circuit as the magnetic pickup to charge a rechargeablenickel cadmium battery.

U.S. Pat. No. 5,279,607, to Schentag, et al., “Telemetry capsule andprocess,” whose disclosure is incorporated herein by reference,describes an ingestible capsule and a process for delivery, particularlyrepeatable delivery, of a medicament to the alimentary canal. Theingestible capsule is essentially non-digestible capsule, which containsan electric energy emitting means, a radio signal transmitting means, amedicament storage means and a remote actuatable medicament releasingmeans. The capsule signals a remote receiver as it progresses throughthe alimentary tract in a previously mapped route and upon reaching aspecified site is remotely triggered to release a dosage of medicament.

Similarly, U.S. Pat. No. 5,395,366, to D'Andrea et al., entitled,“Sampling capsule and process,” whose disclosure is incorporated hereinby reference, describes a similar ingestible capsule and a process forsampling of fluids in the to the alimentary canal.

U.S. Pat. No. 5,604,531, to Iddan, et al., entitled, “In vivo videocamera system,” whose disclosure is incorporated herein by reference,describes a video camera system, encapsulated within an ingestible pill,arranged to pass through the entire digestive tract, operating as anautonomous video endoscope. The ingestible pill includes a camera systemand an optical system for imaging an area of interest onto the camerasystem, and a transmitter, which relays the video output of the camerasystem to an extracorporeal reception system. A light source is locatedwithin a borehole of the optical system.

Similarly, U.S. Patent Application 20010035902, to Iddan, G. J., et al.,entitled, “Device and system for in vivo imaging,” Whose disclosure isincorporated herein by reference, describes a system and method forobtaining in vivo images. The system contains an imaging system and anultra low power radio frequency transmitter for transmitting signalsfrom the CMOS imaging camera to a receiving system located outside apatient. The imaging system includes at least one CMOS imaging camera,at least one illumination source for illuminating an in vivo site and anoptical system for imaging the in vivo site onto the CMOS imagingcamera.

U.S. Pat. No. 6,324,418, to Crowley, et al., entitled, “Portable tissuespectroscopy apparatus and method,” whose disclosure is incorporatedherein by reference, describes a portable tissue spectroscopy apparatusincluding at least one light source, at least one light detector, apower source and a controller module, all disposed inside a housing thatis insertable inside a body. The housing may be in the form of ahand-holdable probe or in the form of a capsule that can be swallowed orimplanted in the body. The probe further includes a display mounted at aproximal end of the housing for displaying tissue characteristics. Thecapsule further includes a transmitter mounted inside the capsule and areceiver placed outside the body for transmitting signals representativeof tissue characteristics to a remote receiver.

The capsule includes one or more light emitters and one or more lightdetectors. The light detectors may be located in various places withinthe housing for detecting spectroscopic properties from various tissuesnear the capsule. The capsule may further include other types ofemitters and sensors. The additional emitters and sensors, for example,can relate to electromagnetic radiation, pressure, temperature, x-rayradiation and/or heat. In one embodiment, the capsule further comprisesan acoustic transmitter and a receiver for measuring flow of fluid orfor detecting echo location of the capsule. In another embodiment, thecapsule further includes diagnostic sensors such as monitoringelectrodes, pressure sensors and temperature sensors.

U.S. Pat. No. 5,415,1818, to Hogrefe, et al., entitled, “AM/FMmulti-channel implantable/ingestible biomedical monitoring telemetrysystem,” whose disclosure is incorporated herein by reference, describesa wireless multi-channel circuit for telemetering signals representingphysiological values from a point in a human body to a receiver outsideof the body. The two signals, S1 and S2, other than the temperaturesignal are used to provide two frequency modulated signals summed by anamplifier with the summed FM signal then being applied to amplitudemodulate a carrier whose frequency varies as a function of temperature.The resulting FM/AM signal is telemetered inductively outside of thebody to an external receiver. Appropriate demodulation, filter, andshaping circuits within the external circuit detect the FM signals andthus produce three independent frequencies two of which are the originalphysiological variables and the third a function of local temperature.Real time plot of the two physiological variables can be obtained usingFM discriminators while the temperature dependent frequency is bestmonitored by a counter.

Similarly, U.S. Pat. No. 5,842,977 to Lesho, et al., entitled,“Multi-channel pill with integrated optical interface,” whose disclosureis incorporated herein by reference, describes an optical interfaceincorporated into a multi-channel telemetry device, used to provide datarepresenting physiological conditions.

Methods of tracking ingestible devices, such as radio pills, are known.U.S. Pat. No. 5,279,607, to Schentag, et al., entitled, “Telemetrycapsule and process,” and U.S. Pat. No. 5,395,366, to D'Andrea et al.,entitled, “Sampling capsule and process,” described hereinabove, includeextracorporeal apparatus having a plurality of antennae, used todetermine the geographic position of the capsule within thegastrointestinal tract. For example, at least three antennae, located atdifferent distances from the point source, and dedicated algorithms maybe used to determine the precise location of the capsule, at any time.

U.S. Pat. No. 6,082,366 to Andrii et al., entitled, “Method andarrangement for determining the position of a marker in an organiccavity,” whose disclosure is incorporated herein by reference, describea method for pinpointing a marker such as an ingestible capsule. Themethod requires that the patient be positioned within a magnetic field,for example, as used for MRI imaging.

Notwithstanding the high level of sophistication of the aforementionedsystems, gastrointestinal pathologies, and particularly, occult tumorshave remained elusive in medical diagnosis. There is thus a widelyrecognized need for, and it would be highly advantageous to have, adevice and method for detecting pathologies in the gastrointestinaltract devoid of the above limitations.

SUMMARY OF THE INVENTION

According to an aspect of the present invention there is provided aningestible device, arranged for traveling within a gastrointestinaltract of a body, comprising:

-   -   a probe, operative to perform, along said gastrointestinal        tract, a diagnostic image by nuclear radiation of a        radiopharmaceutical,    -   data-handling apparatus, in signal communication with said        probe, for receiving and handling imaging data, generated by        said probe;    -   a power source, for powering said probe and data-handling        apparatus; and    -   a shell, which encapsulates said probe, data-handling apparatus,        and power source within.

According to an additional aspect of the present invention, said probecomprises a nuclear-radiation detector, arranged for detecting gamma andbeta radiation.

According to still an additional aspect of the present invention, saidnuclear-radiation detector is not collimated, to detect nuclearradiation impinging at any angle.

According to yet an additional aspect of the present invention, saidnuclear-radiation detector is gated to a narrow energy range, associatedwith a particular radioisotope.

According to still an additional aspect of the present invention, saidnuclear-radiation detector comprises at least two crystals.

According to yet an additional aspect of the present invention, each ofsaid at least two crystals is gated to a different narrow energy range,associated with a different radioisotope.

According to still an additional aspect of the present invention, saidat least two crystals are a predetermined distance apart, in thedirection of travel, and are operative to evaluate an incrementaldistance traveled within said gastrointestinal tract, during a periodΔT, by cross correlating nuclear radiation striking said at least twocrystals at a time T and at a later time T+ΔT.

According another aspect of the present invention, said probe comprisesa photodetector, arranged to detect scintillation produced by ascintillation liquid responsive to nuclear radiation of saidradiopharmaceutical.

According to an additional aspect of the present invention, saidphotodetector comprises at least two photo-sensing diodes, arranged apredetermined distance apart, in the direction of travel, operative toevaluate an incremental distance traveled within said gastrointestinaltract, during a period ΔT, by cross correlating scintillation strikingsaid photo-sensing diodes at a time T and at a later time T+ΔT.

According to an aspect of the present invention there is provided aningestible device, arranged for traveling within a gastrointestinaltract of a body, comprising:

-   -   a probe, comprising a photodetector, operative to perform, along        said gastrointestinal tract, a diagnostic image by optical        fluorescence of a fluorescing-pharmaceutical;    -   a laser light source, of a wavelength which substantially        matches at least one absorption peak of said        fluorescing-pharmaceutical;    -   data-handling apparatus, in signal communication with said        probe, for receiving and handling imaging data, generated by        said probe;    -   a power source, for powering said probe, light source, and        data-handling apparatus; and    -   a shell, which encapsulates said probe, light source,        data-handling apparatus, and power source within.

According to an additional aspect of the present invention, saidphotodetector comprises at least two photo-sensing diodes, arranged apredetermined distance apart, in the direction of travel, operative toevaluate an incremental distance traveled within said gastrointestinaltract, during a period ΔT, by cross correlating fluorescence strikingsaid photo-sensing diodes at a time T and at a later time T+ΔT.

According to still an additional aspect of the present invention, saidingestible device further includes at least two reflected-lightphoto-sensing diodes, arranged a predetermined distance apart, in thedirection of travel, operative to evaluate an incremental distancetraveled within said gastrointestinal tract, during a period ΔT, bycross correlating reflected light striking said reflected-lightphoto-sensing diodes at a time T and at a later time T+ΔT.

According to an aspect of the present invention there is provided aningestible device, arranged for traveling within a gastrointestinaltract of a body, comprising:

-   -   a probe, comprising a photodetector, operative to perform, along        said gastrointestinal tract, a diagnostic image by optical        fluorescence of a bare gastrointestinal-tract tissue;    -   a laser light source, of a wavelength which substantially        matches an absorption peak of said bare gastrointestinal-tract        tissue;    -   data-handling apparatus, in signal communication with said        probe, for receiving and handling imaging data, generated by        said probe;    -   a power source, for powering said probe, light source, and        data-handling apparatus; and    -   a shell, which encapsulates said probe, light source,        data-handling apparatus, and power source within,    -   wherein said photodetector comprises at least two photo-sensing        diodes, arranged a predetermined distance apart, in the        direction of travel, operative to evaluate an incremental        distance traveled within said gastrointestinal tract, during a        period ΔT, by cross correlating fluorescence striking said        photo-sensing diodes at a time T and at a later time T+ΔT.

According to an additional aspect of the present invention, saidingestible device further includes at least two reflected-lightphoto-sensing diodes, adapted to sense reflected light from said laserlight source, arranged a predetermined distance apart, in the directionof travel, operative to evaluate an incremental distance traveled withinsaid gastrointestinal tract, during a period ΔT, by cross correlatingreflected light striking said reflected-light photo-sensing diodes at atime T and at a later time T+ΔT.

According to an aspect of the present invention there is provided aningestible device, arranged for traveling within a gastrointestinaltract of a body, comprising:

-   -   a probe, comprising a thermography detector, operative to        perform, along said gastrointestinal tract, a diagnostic image        by infrared thermography;    -   data-handling apparatus, in signal communication with said        probe, for receiving and handling imaging data, generated by        said probe;    -   a power source, for powering said probe and data-handling        apparatus; and    -   a shell, which encapsulates said probe, data-handling apparatus,        and power source within.

According to an additional aspect of the present invention, saidthermography detector comprises at least two photo-sensing diodes,arranged a predetermined distance apart, in the direction of travel,operative to evaluate an incremental distance traveled within saidgastrointestinal tract, during a period ΔT, by cross correlatinginfrared radiation striking said photo-sensing diodes at a time T and ata later time T+ΔT.

According to an aspect of the present invention there is provided aningestible device, arranged for traveling within a gastrointestinaltract of a body, comprising:

-   -   a thermocouple probe, operative to perform, along said        gastrointestinal tract, a diagnostic image by        temperature-differences;    -   data-handling apparatus, in signal communication with said        probe, for receiving and handling imaging data, generated by        said probe;    -   a power source, for powering said probe and data-handling        apparatus; and    -   a shell, which encapsulates said probe, data-handling apparatus,        and power source within.

According to an aspect of the present invention there is provided aningestible device, arranged for traveling within a gastrointestinaltract of a body, comprising:

-   -   an impedance probe, operative to perform, along said        gastrointestinal tract, a diagnostic image by impedance;    -   data-handling apparatus, in signal communication with said        probe, for receiving and handling imaging data, generated by        said probe;    -   a power source, for powering said probe and data-handling        apparatus; and    -   a shell, which encapsulates said probe, data-handling apparatus,        and power source within.

According to an aspect of the present invention there is provided aningestible device, arranged for traveling within a gastrointestinaltract of a body, comprising:

-   -   an ultrasound probe, operative to perform, along said        gastrointestinal tract, a diagnostic image by ultrasound        reflection;    -   data-handling apparatus, in signal communication with said        probe, for receiving and handling imaging data, generated by        said probe;    -   a power source, for powering said probe and data-handling        apparatus; and    -   a shell, which encapsulates said probe, data-handling apparatus,        and power source within.

According to an aspect of the present invention there is provided aningestible device, arranged for traveling within a gastrointestinaltract of a body, comprising:

-   -   an MRI probe, operative to perform, along said gastrointestinal        tract, a diagnostic image by magnetic resonance;    -   data-handling apparatus, in signal communication with said        probe, for receiving and handling imaging data, generated by        said probe;    -   a power source, for powering said probe and data-handling        apparatus; and    -   a shell, which encapsulates said probe, data-handling apparatus,        and power source within.

According to an aspect of the present invention there is provided aningestible device, arranged for traveling within a gastrointestinaltract of a body, comprising:

-   -   at least two probes, each operative to perform, along said        gastrointestinal tract, a diagnostic image selected from the        group, which consists of nuclear radiation of a        radiopharmaceutical, scintillation of a scintillation liquid,        responsive to nuclear radiation of a radiopharmaceutical,        optical fluorescence of a fluorescing-pharmaceutical, optical        fluorescence of a bare gastrointestinal-tract tissue, infrared        thermography, temperature-differences, impedance, ultrasound        reflection, magnetic resonance, and video, wherein each probe is        operative to perform a different diagnostic image;    -   data-handling apparatus, in signal communication with said        probes, for receiving and handling imaging data, generated by        said probes;    -   a power source, for powering said probes and said data-handling        apparatus; and    -   a shell, which encapsulates said probes, data-handling        apparatus, and power source within.

According to an additional aspect of the present invention, saidingestible device further includes a coating, selected from the groupconsisting of a candy-like coating, a biologically inert coating whichis replaced between uses, and a biologically inert coating which isreplaced between uses, covered with a candy-like coating.

According to still an additional aspect of the present invention, saiddata-handling apparatus comprises a transmitter, communicable with saidprobe and in signal communication with extracorporeal apparatus.

According to yet an additional aspect of the present invention, saidtransmitter comprises a piezoelectric transducer.

According to still an additional aspect of the present invention, saidpiezoelectric transducer is further arranged for tracking saidingestible device within said gastrointestinal tract, in tandem with atleast three extracorporeal piezoelectric transducers, at differentlocations, in direct contact with said body, based on the time of signaltravel from each of said extracorporeal transducer to said ingestibledevice and back.

According to yet an additional aspect of the present invention, saidtransmitter comprises an RF transmitter.

According to still an additional aspect of the present invention, saidtransmitter is further arranged for tracking said ingestible devicewithin said gastrointestinal tract, in tandem with at least threeextracorporeal RF receivers.

According to yet an additional aspect of the present invention, saidtransmitter comprises a multi-channel transmitter.

According to still an additional aspect of the present invention, saidtransmitter produces a reference signal at predetermined time intervals.

According to yet an additional aspect of the present invention, saidreference signal further includes identifying information of said body.

According to still an additional aspect of the present invention, saidingestible device further includes a receiver.

According to yet an additional aspect of the present invention, saidreceiver comprises a multi-channel receiver.

According to still an additional aspect of the present invention, saiddata-handling apparatus comprises a computing means.

According to yet an additional aspect of the present invention, saidingestible device further includes a memory, for recording diagnosticinformation produced by said probe, therein.

According to still an additional aspect of the present invention, saidmemory is a removable data-storage implement.

According to yet an additional aspect of the present invention, saidpower source comprises an energizable power source.

According to still an additional aspect of the present invention, saidenergizable power source comprises a piezoelectric transducer.

According to yet an additional aspect of the present invention, saidingestible device further includes a tracking means, for tracking saidingestible device within said gastrointestinal tract.

According to still an additional aspect of the present invention, saidtracking is performed vis a vis an extracorporeal reference system.

According to yet an additional aspect of the present invention, saidtracking means comprises at least one acceleration sensor, which sensesaccelerations in at least three degrees of freedom, with respect to aset of three mutually perpendicular coordinate axes.

According to another aspect of the present invention, said trackingmeans comprises at least at least three acceleration sensors, eachsensing accelerations along a single axis of a set of three mutuallyperpendicular coordinate axes.

According to still another aspect of the present invention, saidtracking means comprises a magnetic tracking and location system.

According to yet another aspect of the present invention, said trackingmeans includes a piezoelectric transducer, operable in tandem with atleast three extracorporeal piezoelectric transducers, at differentlocations, in direct contact with said body, for tracking based on thetime of signal travel from each of said extracorporeal transducer tosaid ingestible device and back.

According to another aspect of the present invention, said tracking isperformed vis a vis the walls of said gastrointestinal tract.

According to an additional aspect of the present invention, saidtracking means comprises at least one roller, adapted to roll againstthe tissue of said gastrointestinal tract, wherein said at least oneroller is in communication with a counter, and wherein the number ofrevolutions made by said at least one roller indicate the lengthtraveled by said ingestible device.

According to still an additional aspect of the present invention, saidtracking means includes at least two piezoelectric transducers, arrangeda predetermined distance apart, in the direction of travel, operative toevaluate an incremental distance traveled within said gastrointestinaltract, during a period ΔT, by cross correlating ultrasound reflection ofan ultrasound pulse, originating from one of said at least twopiezoelectric transducers, striking said at least two piezoelectrictransducers, at a time T and at a later time T+ΔT.

According to yet an additional aspect of the present invention, saidingestible device further includes a plurality of piezoelectrictransducers, to enhance the cross correlation.

According to still an additional aspect of the present invention, saidtracking means includes a light source and at least two photo-sensingdiodes, arranged a predetermined distance apart, in the direction oftravel, operative to evaluate an incremental distance traveled withinsaid gastrointestinal tract, during a period ΔT, by cross correlatingreflected light striking said photo-sensing diodes at a time T and at alater time T+ΔT.

According to yet an additional aspect of the present invention, saidingestible device further includes a plurality of photo-sensing diodesto enhance the cross correlation.

According to still an additional aspect of the present invention, saidingestible device is disposable, and needs not be retrieved.

According to an aspect of the present invention there is provided atissue diagnostic system, comprising:

-   -   an ingestible device; and    -   extracorporeal apparatus, comprising:        -   at least one extracorporeal receiver;        -   an extracorporeal computing means; and        -   an extracorporeal power source.

According to an additional aspect of the present invention, saidextracorporeal apparatus further includes a replaceable interface.

According to still an additional aspect of the present invention, saidat least one extracorporeal receiver further includes at least threeextracorporeal receivers, for tracking said ingestible device.

According to yet an additional aspect of the present invention, said atleast three extracorporeal receivers further includes at least threepiezoelectric-transducer patch-sensor devices.

According to another aspect of the present invention, said at least oneextracorporeal receiver comprises an RF receiver.

According to an additional aspect of the present invention, said atleast one extracorporeal receiver comprises a multi-channel receiver.

According to still an additional aspect of the present invention, saidsystem further comprises an RF transmitter.

According to yet an additional aspect of the present invention, saidingestible device further comprises at least one intracorporealacceleration sensor, which senses accelerations in at least threedegrees of freedom, with respect to a set of three mutuallyperpendicular coordinate axes, and said extracorporeal apparatus furthercomprises at least one extracorporeal acceleration sensor, for sensingaccelerations of said body, in at least three degrees of freedom, withrespect to a set of three mutually perpendicular coordinate axes, inorder to correct measurements of said intracorporeal accelerationsensor, for movements of said body.

According to an aspect of the present invention there is provided amethod of performing tissue diagnosis within a gastrointestinal tract ofa body, comprising:

-   -   providing an ingestible device comprising a probe, operative to        perform, along said gastrointestinal tract, a diagnostic image        by nuclear radiation of a radiopharmaceutical;    -   administrating said radiopharmaceutical;    -   ingesting said ingestible device, a predetermined time after        said administrating said radiopharmaceutical;    -   producing diagnostic signals with said probe, as said ingestible        device travels in said gastrointestinal tract, thus forming said        diagnostic image; and    -   recording information of said diagnostic image.

According to an additional aspect of the present invention, said probecomprises a nuclear-radiation detector, arranged for detecting gamma andbeta radiation.

According to still an additional aspect of the present invention, saidnuclear-radiation detector comprises at least two crystals.

According to yet an additional aspect of the present invention, saidmethod further includes gating each of said crystals to a differentnarrow energy range, associated with a different radioisotope.

According to still an additional aspect of the present invention, saidmethod further includes using the clock-like property of nuclearradiation to identify a pathological site, by an activity ratio of atleast two radioisotopes.

According to yet an additional aspect of the present invention, said atleast two crystals are arranged a predetermined distance apart, in thedirection of travel, and wherein said method further includes evaluatingthe distance traveled within said gastrointestinal tract, by crosscorrelating nuclear radiation striking said crystals at a time T and ata later time T+ΔT.

According another aspect of the present invention, said probe comprisesa photodetector, wherein said method further includes administrating ascintillation liquid, a predetermined time after said administratingsaid radiopharmaceutical and a predetermined time before said ingestingsaid ingestible device, and wherein said producing diagnostic signalswith said probe further includes detecting scintillation, produced bysaid scintillation liquid, responsive to nuclear radiation of saidradiopharmaceutical, thus forming said diagnostic image.

According to an additional aspect of the present invention, said probecomprises at least two photo-sensing diodes, arranged a predetermineddistance apart, in the direction of travel, and said method furtherincludes evaluating the distance traveled within said gastrointestinaltract, by cross correlating scintillation striking said photo-sensingdiodes at a time T and at a later time T+ΔT.

According to an aspect of the present invention there is provided amethod of performing tissue diagnosis within a gastrointestinal tract,comprising:

-   -   providing an ingestible device comprising a laser light source        and a probe, comprising a photodetector, operative to perform,        along said gastrointestinal tract, a diagnostic image by optical        fluorescence of a fluorescing-pharmaceutical, wherein said laser        light source is operative at a wavelength that substantially        matches an absorption peak of said fluorescing-pharmaceutical;    -   administrating said fluorescing-pharmaceutical;    -   ingesting said ingestible device, a predetermined time after        said administrating said fluorescing-pharmaceutical;    -   producing diagnostic signals with said probe, as said ingestible        device travels in said gastrointestinal tract, thus forming said        diagnostic image; and    -   recording information of said diagnostic image.

According to an additional aspect of the present invention, saidphotodetector comprises at least two photo-sensing diodes, arranged apredetermined distance apart, in the direction of travel, and saidmethod further includes evaluating the distance traveled within saidgastrointestinal tract, by cross correlating fluorescence striking saidphoto-sensing diodes at a time T and at a later time T+ΔT.

According to still an additional aspect of the present invention, saidingestible device further includes at least two reflected-lightphoto-sensing diodes, arranged a predetermined distance apart, in thedirection of travel, and said method further includes evaluating thedistance traveled within said gastrointestinal tract, by crosscorrelating reflected light striking said reflected-light photo-sensingdiodes at a time T and at a later time T+ΔT.

According to an aspect of the present invention there is provided amethod of performing tissue diagnosis within a gastrointestinal tract,comprising:

-   -   providing an ingestible device comprising a laser light source        and a probe, comprising a photodetector, operative to perform,        along said gastrointestinal tract, a diagnostic image by optical        fluorescence of a bare tissue, wherein said laser light source        is operative at a wavelength that substantially matches an        absorption peak of said bare gastrointestinal-tract tissue;    -   ingesting said ingestible device;    -   producing diagnostic signals with said probe, as said ingestible        device travels in said gastrointestinal tract, thus forming said        diagnostic image; and    -   recording information of said diagnostic image,    -   wherein said photodetector comprises at least two photo-sensing        diodes, arranged a predetermined distance apart, in the        direction of travel, and wherein said method further includes        evaluating the distance traveled within said gastrointestinal        tract, by cross correlating fluorescence striking said        photo-sensing diodes at a time T and at a later time T+ΔT.

According to an additional aspect of the present invention, saidingestible device further includes at least two reflected-lightphoto-sensing diodes, arranged a predetermined distance apart, in thedirection of travel, and wherein said method further includes evaluatingthe distance traveled within said gastrointestinal tract, by crosscorrelating reflected light striking said reflected-light photo-sensingdiodes at a time T and at a later time T+ΔT.

According to an aspect of the present invention there is provided amethod of performing tissue diagnosis within a gastrointestinal tract,comprising:

-   -   providing an ingestible device comprising a probe, which further        comprises a thermography detector, operative to perform, along        said gastrointestinal tract, a diagnostic image by infrared        thermography;    -   ingesting said ingestible device;    -   producing diagnostic signals with said probe, as said ingestible        device travels in said gastrointestinal tract, thus forming said        diagnostic image; and    -   recording information of said diagnostic image.

According to an additional aspect of the present invention, saidthermography detector further comprises at least two photo-sensingdiodes, arranged a predetermined distance apart, in the direction oftravel, and wherein said method further includes evaluating the distancetraveled within said gastrointestinal tract, by cross correlatinginfrared radiation striking said photo-sensing diodes at a time T and ata later time T+ΔT.

According to an aspect of the present invention there is provided amethod of performing tissue diagnosis within a gastrointestinal tract,comprising:

-   -   providing an ingestible device comprising a thermocouple probe,        operative to perform, along said gastrointestinal tract, a        diagnostic image by temperature-differences;    -   ingesting said ingestible device;    -   producing diagnostic signals with said probe, as said ingestible        device travels in said gastrointestinal tract, thus forming said        diagnostic image; and    -   recording information of said diagnostic image.

According to an aspect of the present invention there is provided amethod of performing tissue diagnosis within a gastrointestinal tract,comprising:

-   -   providing an ingestible device comprising an impedance probe,        operative to perform, along said gastrointestinal tract, a        diagnostic image by impedance;    -   ingesting said ingestible device;    -   producing diagnostic signals with said probe, as said ingestible        device travels in said gastrointestinal tract, thus forming said        diagnostic image; and    -   recording information of said diagnostic image.

According to an aspect of the present invention there is provided amethod of performing tissue diagnosis within a gastrointestinal tract,comprising:

-   -   providing an ingestible device comprising an ultrasound probe,        operative to perform, along said gastrointestinal tract, a        diagnostic image by ultrasound reflection;    -   ingesting said ingestible device;    -   producing diagnostic signals with said probe, as said ingestible        device travels in said gastrointestinal tract, thus forming said        diagnostic image; and    -   recording information of said diagnostic image.

According to an aspect of the present invention there is provided amethod of performing tissue diagnosis within a gastrointestinal tract,comprising:

-   -   providing an ingestible device comprising an MRI probe,        operative to perform, along said gastrointestinal tract, a        diagnostic image by magnetic resonance;    -   ingesting said ingestible device;    -   producing diagnostic signals with said probe, as said ingestible        device travels in said gastrointestinal tract, thus forming said        diagnostic image; and    -   recording information of said diagnostic image.

According to an additional aspect of the present invention, said methodfurther includes resonating at a frequency of a contrast agent that hasbeen administered to said body.

According to an aspect of the present invention there is provided amethod of performing tissue diagnosis within a gastrointestinal tract,comprising:

-   -   providing an ingestible device comprising at least two probes,        each operative to perform, along said gastrointestinal tract, a        diagnostic image selected from the group, which consists of        nuclear radiation of a radiopharmaceutical, scintillation of a        scintillation liquid, responsive to nuclear radiation of a        radiopharmaceutical, optical fluorescence of a        fluorescing-pharmaceutical, optical fluorescence of a bare        gastrointestinal-tract tissue, infrared thermography,        temperature-differences, impedance, ultrasound reflection,        magnetic resonance, and video, wherein each probe is operative        to perform a different diagnostic image;    -   ingesting said ingestible device;    -   producing diagnostic signals with said probes, as said        ingestible device travels in said gastrointestinal tract, thus        forming said diagnostic images; and    -   recording information of said diagnostic images.

According to an additional aspect of the present invention, saiddiagnostic image comprises diagnostic information as a function of time.

According to yet an additional aspect of the present invention, saiddiagnostic image comprises diagnostic information as a function ofdistance traveled by said ingestible device.

According to still an additional aspect of the present invention, saidrecording further includes transmitting said informationextracorporeally, and recording said information by extracorporealapparatus.

According to another aspect of the present invention, said recordingfurther includes recording said information within said ingestibledevice.

According to still an additional aspect of the present invention, saidmethod further includes administrating a pharmaceutical a predeterminedtime prior to said ingesting said ingestible device.

According to still an additional aspect of the present invention, saidmethod further includes screening a large population.

According to still an additional aspect of the present invention, saidmethod further includes screening for gastrointestinal-tract neoplasm.

According to still an additional aspect of the present invention, saidmethod further includes diagnosing for a suspected pathology.

According to still an additional aspect of the present invention, saidsuspected pathology is malignant.

According to still an additional aspect of the present invention, saidsuspected pathology is nonmalignant.

According to an aspect of the present invention there is provided amethod of locating a site in a gastrointestinal tract, comprising:

-   -   evaluating a distance from a reference point to said site, by        tracking an ingestible device within said gastrointestinal        tract, vis a vis the walls of said gastrointestinal tract; and    -   invasively measuring said distance along said gastrointestinal        tract from said reference point to said site.

According to an additional aspect of the present invention, saidevaluating said distance further includes:

-   -   providing at least two sensors, arranged a predetermined        distance apart, in the direction of travel;    -   cross correlating a parameter sensed by said at least two        sensors, at a time T and at a later time T+ΔT;    -   determining an incremental distance traveled by said ingestible        device within said gastrointestinal tract, during period ΔT; and    -   summing incremental distances between the time said ingestible        device passed by said reference point and the time said        ingestible device passed by said site, to obtain said distance.

According to still an additional aspect of the present invention, saidparameter, sensed by said at least two sensors, is selected from thegroup consisting of nuclear radiation of a radiopharmaceutical,scintillation light produced by a scintillation liquid, responsive tonuclear radiation of a radiopharmaceutical, optical fluorescence,reflected light, infrared radiation, temperature differences, impedance,and ultrasound reflection.

According to another aspect of the present invention, said evaluatingsaid distance further includes:

-   -   employing at least one roller, arranged to roll over the walls        of said gastrointestinal tract; and    -   employing a counter, in communication with said at least one        roller, for counting the number of revolutions made by said at        least one roller, between the time said ingestible device passed        by said reference point and the time said ingestible device        passed by said site.

According to an aspect of the present invention there is provided amethod of locating a site in a gastrointestinal tract, comprising:

-   -   estimating a distance from a reference point to said site, by        tracking an ingestible device within said gastrointestinal        tract, vis a vis an extracorporeal reference system; and    -   invasively measuring said distance along said gastrointestinal        tract from said reference point to said site.

According to an additional aspect of the present invention, said methodfurther includes:

-   -   tracking an ingestible device within said gastrointestinal        tract, to obtain instantaneous x; y; z; values vis a vis said        extracorporeal reference system;    -   estimating an incremental distance traveled by said ingestible        device within said gastrointestinal tract, during period ΔT; and    -   summing estimated incremental distances between the time said        ingestible device passed by said reference point and the time        said ingestible device passed by said site, to estimate said        distance.

According to an additional aspect of the present invention, saidtracking is selected from the group consisting of tracking with anintracorporeal RF transmitter and three extracorporeal RF receivers,tracking with an intracorporeal piezoelectric transducer and threeextracorporeal piezoelectric transducer, tracking with at least oneacceleration sensor, and tracking with a magnetic tracking and locationsystem.

According to an aspect of the present invention there is provided amethod of identifying a pathology, using a clock-like property ofradioisotopes, comprising:

-   -   providing a nuclear-radiation detector arranged for        distinguishing between at least two forms of radiation,        associated with at least two radioisotopes;    -   administering a radiopharmaceutical which includes said at least        two radioisotopes;    -   performing diagnostic images by nuclear radiation for each of        said at least two radioisotopes;    -   evaluating an activity ratio for said at least two        radioisotopes; and identifying said pathology, by an observed        change in said activity ratio.

The present invention successfully addresses the shortcomings of thepresently known configurations, by providing a an ingestible device,adapted to travel in the gastrointestinal tract and perform a diagnosticimage of tissue therein. The diagnostic image comprises diagnosticinformation as a function of time, for example, since the ingestion ofthe ingestible device, or diagnostic information as a function ofdistance traveled by the ingestible device. Specifically, the ingestibledevice may be arranged to perform a diagnostic image of any of thefollowing, or a combination thereof:

-   i. nuclear radiation of a radiopharmaceutical;-   ii. scintillation of a scintillation liquid, responsive to nuclear    radiation of a radiopharmaceutical;-   iii. optical fluorescence of a fluorescing-pharmaceutical or of bare    gastrointestinal-tract tissue;-   iv. infrared radiation of the gastrointestinal-tract tissue, by    infrared thermography;-   v. temperature-differences along the gastrointestinal-tract tissue;-   vi. impedance of the gastrointestinal-tract tissue;-   vii. ultrasound reflection of the gastrointestinal-tract tissue; and-   viii. magnetic resonance of the gastrointestinal-tract tissue.

Additionally, the ingestible device may be adapted for general screeningof a large population, as well as for specific diagnoses of suspectedpathologies.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention is herein described, by way of example only, withreference to the accompanying drawings. With specific reference now tothe drawings in detail, it is stressed that the particulars shown are byway of example and for purposes of illustrative discussion of thepreferred embodiments of the present invention only, and are presentedin the cause of providing what is believed to be the most useful andreadily understood description of the principles and conceptual aspectsof the invention. In this regard, no attempt is made to show structuraldetails of the invention in more detail than is necessary for afundamental understanding of the invention, the description taken withthe drawings making apparent to those skilled in the art how the severalforms of the invention may be embodied in practice.

In the drawings:

FIGS. 1A-1C schematically illustrate an overview of a diagnostic system,in accordance with the present invention;

FIGS. 2A-2B schematically illustrate an ingestible device, in accordancewith a preferred embodiment of the present invention;

FIGS. 3A-3D schematically illustrate an ingestible device, comprising aprobe arranged as a nuclear-radiation detector, in accordance with apreferred embodiment of the present invention;

FIGS. 4A-4D schematically illustrate an ingestible device, comprisingprobe, arranged as a nuclear-radiation detector, in accordance withanother preferred embodiment of the present invention;

FIG. 5 schematically illustrates an ingestible device, comprising aprobe arranged as at least one photo-detector, in accordance with yetanother preferred embodiment of the present invention;

FIG. 6 schematically illustrates an ingestible device, comprising aprobe arranged as at least one detector optical fluorescence and a lightsource, in accordance with still another preferred embodiment of thepresent invention;

FIG. 7 schematically illustrates an ingestible device, comprising aprobe, arranged for infrared thermography, in accordance with yetanother preferred embodiment of the present invention;

FIGS. 8A and 8B schematically illustrate the operation of an ingestibledevice comprising at least one thermocouple probe, in accordance withyet another preferred embodiment of the present invention;

FIGS. 9A and 9B schematically illustrate the operation of an ingestibledevice comprising at least one impedance probe, in accordance with stillanother preferred embodiment of the present invention;

FIGS. 10A and 10B schematically illustrate ingestible devices, inaccordance with still other preferred embodiments of the presentinvention;

FIG. 11 schematically illustrates an ingestible device comprising anultrasound probe, in accordance with yet another preferred embodiment ofthe present invention;

FIGS. 12A-12C schematically illustrate a probe arranged as an MRI probe,in accordance with yet another preferred embodiment of the presentinvention;

FIGS. 13A-13B schematically illustrate a tracking system, in accordancewith a preferred embodiment of the present invention;

FIGS. 14A-14C schematically illustrate a tracking system, in accordancewith another preferred embodiment of the present invention;

FIG. 15 schematically illustrates a tracking system, in accordance witha another preferred embodiment of the present invention;

FIGS. 16A-16B schematically illustrate a tracking system, in accordancewith still another preferred embodiment of the present invention;

FIG. 17 schematically illustrates a tracking system, in accordance withyet another preferred embodiment of the present invention;

FIG. 18 schematically illustrates a tracking system, in accordance withstill another preferred embodiment of the present invention;

FIGS. 19A-19B schematically illustrate a tracking system, in accordancewith yet another preferred embodiment of the present invention; and

FIG. 20 schematically illustrates an ingestible device, arranged forgeneral screening, in accordance with a preferred embodiment of thepresent invention.

FIG. 21 schematically illustrates an ingestible device, in accordancewith a preferred embodiment of the present invention;

FIG. 22 schematically illustrates a device for detector calibration, inaccordance with a preferred embodiment of the present invention;

FIG. 23 schematically illustrates a method of detector calibration, inaccordance with a preferred embodiment of the present invention; and

FIG. 24 schematically illustrates a method of calculating the depth of aradiation source, in accordance with a preferred embodiment of thepresent invention.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention is of an ingestible device, adapted to travel inthe gastrointestinal tract and perform a diagnostic image of tissuetherein. The diagnostic image comprises diagnostic information as afunction of time, for example, since the ingestion of the ingestibledevice, or diagnostic information as a function of distance traveled bythe ingestible device. Specifically, the ingestible device may bearranged to perform a diagnostic image of any of the following, or acombination thereof:

-   i. nuclear radiation of a radiopharmaceutical;-   ii. scintillation of a scintillation liquid, responsive to nuclear    radiation of a radiopharmaceutical;-   iii. optical fluorescence of a fluorescing-pharmaceutical or of bare    gastrointestinal-tract tissue;-   iv. infrared radiation of the gastrointestinal-tract tissue, by    infrared thermography;-   v. temperature-differences along the gastrointestinal-tract tissue;-   vi. impedance of the gastrointestinal-tract tissue;-   vii. ultrasound reflection of the gastrointestinal-tract tissue; and-   viii. magnetic resonance of the gastrointestinal-tract tissue.

Additionally, the ingestible device may be adapted for general screeningof a large population, on the one hand, and for specific diagnoses ofsuspected pathologies, on the other.

The principles and operation of the ingestible device according to thepresent invention may be better understood with reference to thedrawings and accompanying descriptions.

Before explaining at least one embodiment of the invention in detail, itis to be understood that the invention is not limited in its applicationto the details of construction and the arrangement of the components setforth in the following description or illustrated in the drawings. Theinvention is capable of other embodiments or of being practiced orcarried out in various ways. Also, it is to be understood that thephraseology and terminology employed herein is for the purpose ofdescription and should not be regarded as limiting.

Referring to the drawings, FIGS. 1A-1C schematically illustratecomponents 12, 18, and 20 of a diagnostic system 10, in accordance witha preferred embodiment of the present invention.

Diagnostic system 10 includes an ingestible device 12, adapted to travelwithin a gastrointestinal track 14 of a body 16 and perform diagnosis ofa tissue therein.

Diagnostic system 10 may further include extracorporeal apparatus 18, inwireless communication with ingestible device 12, adapted to be worn bybody 16, or be placed near body 16. Additionally, diagnostic system 10may include a computer station 20.

For example, extracorporeal apparatus 18 may be configured as agirdle-like garment 22, with straps 24 and buckles 26, arranged to beworn around the abdomen of body 16, to closely proximategastrointestinal track 14. Alternatively, apparatus 18 may be worn as anelastic garment, a backpack, a handbag, or the like, or be placed nearbody 16.

Preferably, when worn by body 16, extracorporeal apparatus 18 fartherincludes an interface 15, such as a removable lining 15 or a removablewrapping 15, for providing a replaceable or a washable surface, betweenapparatus 18 and body 16.

Preferably, extracorporeal apparatus 18 includes a power source 28, acomputer means 30, and a related circuitry 32. Additionally, computermeans 30 includes a processor 34 and preferably, a memory 36 and arelated circuitry 33. However, in accordance with the present invention,signal communication within extracorporeal apparatus 18 and (or)computer means 30 may be wireless. Preferably, computer means 30 furtherincludes a removable data storage implement 38, such as a diskette, aminidisk, a CD, a tape or the like.

Apparatus 18 further includes at least one receiver 40, for receivingsignals from ingestible device 12. Additionally, apparatus 18 mayinclude two, or preferably three or more receivers 40, such as 40 _(A),40 _(B), 40 _(C), and possibly also 40 _(D), 40 _(E), and 40 _(F).Communication of with ingestible device 12 may be by RF or by ultrasoundradiation.

Apparatus 18 may further include a transmitter 42, or a transmitter andreceiver system 42, for communicating with computer station 20,preferably, by RF radiation. Alternatively, communication with computerstation 20 may be by cable.

Alternatively or additionally, transmitter 42 may be used for sendinginstructions to ingestible device 12.

Diagnostic system 10 may further include an extracorporeal referencesystem x; y; z, referenced for example, to any one of receivers 40 ofapparatus 18. Additionally, diagnostic system 10 may further include anintracorporeal reference system u; v; w, referenced, for example, to theexit of a stomach 11.

Computer station 20 may be a Personal Computer, a minicomputer, alaptop, or the like. Preferably, computer station 20 includes a datareading implement 44, compatible with removable data-storage implement38 of apparatus 18. Additionally, computer station 20 may include areceiver 46 or a transmitter and receiver system 46, for communicatingwith transmitter and receiver system 42 of apparatus 18, or withingestible device 12. Computer station 20 may also be in communicationwith a network, for example, for accessing databanks and forcontributing to databanks of diagnostic data, as relevant.

Referring further to the drawings, FIGS. 2A-2B schematically illustrateingestible device 12, in accordance with a preferred embodiment of thepresent invention.

As seen in FIG. 2A, ingestible device 12 includes at least one probe 50,operative to perform a diagnostic image of tissue along gastrointestinaltract 14. Ingestible device 12 further includes a distal end 11 and aproximal end 13, with respect to stomach 11 (FIG. 1A). Furthermore,ingestible device 12 defines an axis R, parallel with its direction oftravel.

Additionally, ingestible device 12 includes data-handling apparatus 53,in signal communication with probe 50, arranged for receiving andhandling imaging data generated by probe 50.

Data-handling apparatus 53 may be, for example, a transmitter 54,arranged to transmit data, sensed by probe 50, to at least one receiver40 of extracorporeal apparatus 18 (FIG. 1C), or directly to receiver 46of computer station 20. Transmitter 54 may also transmit a periodicreference signal, which may include identifying details of body 16 andthe date and (or) time of the diagnosis.

In accordance with a preferred embodiment of the present invention,transmitter 54 and at least one receiver 40 (FIG. 1C) are arranged forRF communication, which may further include multichannel communication.For example, data may be transmitted in one channel, and a referencesignal may be transmitted in another. Additionally, where a plurality ofprobes is used in conjunction with ingestible device 12, as will bedescribed below, each probe may be assigned a channel. Alternatively,transmitter 54 may be arranged to communicate with at least one receiver40 by ultrasound radiation.

Ingestible device 12 may further include a power source 52 and a relatedcircuitry 56. However, signal communication within ingestible device 12may be wireless.

Probe 50, data-handling apparatus 53, power source 52 and relatedcircuitry 56 are encapsulated within a shell 58. Shell 58 may be formedof an inert biocompatible material, such as, polycarbonate,polyethylene, natural rubber, silicon, or a composite formed forexample, as an epoxy resin impregnated with glass fibers.

Additionally, shell 58 may be coated with a candy-like coating 59,formed, for example, of crusted sugar, sugared gelatin, chocolate, orthe like.

The overall size of ingestible device 12 should be small enough for easyingestion, for example, about 2 cm in length, and about 1 cm in width.It will be appreciated that smaller dimensions are possible.Additionally, somewhat larger dimensions may be possible.

Preferably, ingestible device 12 is disposable. Ingestible device 12 maybe disposed naturally, by the body, or retrieved for examination, andthen disposed. Alternatively, ingestible device 12 may be retrieved forrepeated use, following cleaning and sterilization.

In accordance with a preferred embodiment of the present embodiment seenin FIG. 2A, device 12 includes a minimal number of components, necessaryfor diagnosis. As such, it is relatively inexpensive, thus suitable as ageneral screening device. Additionally, noise, which may arise frominterference between components, is kept at a minimum.

In accordance with another preferred embodiment of the presentinvention, seen in FIG. 2B, ingestible device 12 is arranged forretrieval and repeated use and further includes a second shell 60.Second shell 60 may be formed, for example, of a thin polycarbon layer,or a similar material, and is replaced between uses, following cleaningand sterilization. Additionally, second shell 60 may comprise acandy-like coating. Second shell 60 is utilized in order to overcome anyuneasiness, associated with ingesting a device that has been through thegastrointestinal tract of another.

Referring further to the drawings, FIGS. 3A-3D schematically illustrateingestible device 12, arranged for imaging nuclear radiation of aradiopharmaceutical, and a method of imaging thereof, in accordance witha preferred embodiment of the present invention. Preferably, probe 50comprises a nuclear-radiation detector 49. Ingestible device 12 mayfurther include transmitter 54, power source 52 and related circuitry56, as has been described hereinabove, in conjunction with FIG. 2A.

Nuclear-radiation detector 49 may comprise at least one Cadmium ZincTelluride crystal or at least one Cadmium Telluride crystal, operativeto detect both gamma and beta radiation. Additionally, two or morecrystals may be employed. These may be obtained from eV Products, PA,USA) 375 Saxonburg Blvd. Saxonburg, Pa. 16056. Alternatively, anothernuclear-radiation detector 49, preferably operative to detect both gammaand beta radiation, may be used, as known.

Preferably, nuclear-radiation detector 49 is not collimated; rather, itis operative to detect nuclear radiation from any directions.Alternatively, nuclear-radiation detector 49 may include ahoneycomb-type collimator, arranged around its circumference, operativeto detect nuclear radiation from any directions. Alternatively, anothercollimator may be used, as known.

Preferably, nuclear-radiation detector 49 is operative to detect nuclearradiation across a wide energy spectrum from about 6.0 KeV to about 1.5MeV, associated with beta and gamma radiation. Alternatively, gating maybe performed to detect radiation at a specific energy range, associatedwith a particular isotope. As an example, nuclear-radiation detector 49may be gated for incoming radiation at an energy of about 28 KeV, whichcorresponds to gamma photons, emitted by I¹²⁵. As another example,nuclear-radiation detector 49 may be gated for incoming radiation at anenergy of about 0.9 MeV, which corresponds to beta energy of P³². Wheretwo or more crystals are used, one may be gated for one energy range,and the other, for another energy range, in order to detect specificradiation emitted by different radioisotopes, for example, to minimizebackground interference.

Preferably, nuclear-radiation detector 49 generates a current pulse thatis proportional to the energy of a detected particle, with sufficienttime resolution to detect each gamma and (or) beta particle separately.Thus, gating may be performed by the electronic circuitry, according tothe particle's energies.

Sometime prior to the ingestion of ingestible device 12, for example,several hours to about two days prior to the ingestion, aradiopharmaceutical is administered to body 16. Preferably,administration is by injection. Alternatively, administration may beoral or intravenous. The radiopharmaceutical may include a monoclonalantibody such as anti-CEA, anti-TAG-72, or another antibody, labeledwith a radioisotope, for example, any one of Technetium Tc^(99m), IodineI¹²⁵, I¹²³, I¹³¹, and I¹³³, Indium In¹¹¹, Gallium Ga⁶⁷, thalium Tl²⁰¹,fluorine F¹⁸ and P³² Among these, Ga⁶⁷, I¹³¹, and P³² emit □ □ □ □radiation.

In accordance with the present invention, □ □ □ □ radiation is ofparticular use, in the small intestine. In water, or body tissue, □ □ □□ radiation has a range of only a few millimeters before it is absorbed.Yet in the small intestine, ingestible device makes contact with thewalls of gastrointestinal tract 14, and when gated to a particular betaenergy, is operative to detect □ □ □ □ radiation, without theinterference of background radiation.

The radiopharmaceutical may include two or more antibodies, each labeledby a different isotope. For example, a cocktail of anti-CEA labeled withany one of I¹²⁵, I¹²³, I¹³¹, I¹³³ or Tc^(99m) and anti-TAG-72 labeledwith Indium In¹¹¹ may be used.

Additionally, the radiopharmaceutical may include a mixture of tworadioisotopes, for example, anti-CEA labeled with I¹³¹ and anti-CEAlabeled with I¹³³.

Preferably, Prior to the ingestion of ingestible device 12, the patientis prepared so that minimal contents are present in gastrointestinaltrack 14.

For illustrative purposes, it is assumed that a pathological site 82exists along gastrointestinal tract 14. The radiopharmaceutical tied topathological specific antibodies is likely to concentrate at site 82,generating nuclear radiation 81.

As ingestible device 12 travels in gastrointestinal tract 14, as seen inFIG. 3A, it transmits data, representing nuclear radiation counts, toextracorporeal computer means 30 (FIG. 1C). Preferably, computer means30 records the incoming data as a function of time, from the time ofingestion.

Preferably, computer means 30 (FIG. 1C) records the data as the numberof counts during a predetermined time interval, or time channel, for allthe time intervals, from the time of ingestion. The predetermined timeintervals may be, for example, 30 seconds, 1 minute, or 10 minutes, oranother predetermined value, and may depend on the expected count rate.For example, if ingestible device 12 takes 70 hours (=4200 minutes) totravel the length of gastrointestinal tract 14, computer means 30 maycollect the data in 4200 channels of 1-minute intervals, or in 420channels of 10-minute intervals, or in any other number of channels thatis predetermined. Data manipulation may later coalesce channels to aidin interpretation. For example, data may be collected and stored in veryfine channels of, for example, 1 second, and later coalesced anddisplayed in channels of 10 minutes.

FIG. 3B schematically illustrates nuclear-radiation counts in 10-minutechannels, at 10 to 12 hours (600-720 minutes) after ingestion, as may begenerated by computer means 30 (FIG. 1C). A statistically significantradiation peak, centered around 640 minutes after ingestion, isindicative of a suspected pathology, such as a neoplastic tissue, atthat location.

Although a location known only as 640 (=10.7 hours) after ingestion isnot necessarily well defined, it is nonetheless somewhat informative.Generally, ingestible device 12 takes about 70 hours or approximately 3days to complete its route. Of these, the later 30 to 50 hours are spentin the colon. Thus a surgeon may estimate that at about 11 hours afteringestion, ingestible device 12 was probably in the small intestine.

A method of identifying the location of pathological site 82 isdescribed hereinbelow, in conjunction with FIGS. 3C and 3D. Alternativemethods of identifying the location of pathological site 82 aredescribed hereinbelow, in conjunction with FIGS. 13A-19B.

As taught by U.S. Pat. No. 5,279,607, to Schentag et al., entitled,“Telemetry Capsule and Process,” and U.S. Pat. No. 5,396,366 to A'Andreaet al., entitled, Sampling capsule and process,” whose disclosures areincorporated herein by reference, at least three receivers, such asreceivers 40 _(A), 40 _(B) and 40 _(C) (FIG. 1C) arranged at differentlocations, and dedicated algorithms, may be used to determine a preciselocation of the source of radiation, transmitter 54 (FIG. 2A) ofingestible device 12, at a given time.

However, due to intrinsic motion of gastrointestinal tract 14 withinbody 16 (FIG. 1A), as part of the digestive process, a precise locationof site 82, with respect to extracorporeal reference system x; y; z, ismeaningless. The same diagnosis, performed a week later, with the sameextracorporeal reference system x; y; z, will produce different x,y,zvalues for site 82.

Nonetheless, a distance L traveled by ingestible device 12, fromintracorporeal reference system u; v; w, for example, the exit ofstomach 11, to site 82, may be estimated, based on instantaneous x; y; zvalues of ingestible device 12. This distance is of value, as a surgeonmay measure, invasively, along gastrointestinal tract 14 and arrive atsite 82.

For this purpose, precise, instantaneous locations of ingestible device12 may be estimated, vis a vis plurality of receivers 40 ofextracorporeal apparatus 18 (FIG. 1C), for each time interval i, bycomputer means 30. Preferably, extracorporeal reference system x; y; z(FIG. 1A) is correlated with the locations of receivers 40, for example,by using one of the receivers as position (0; 0; 0). The instantaneousx,y,z, values of each time interval i may be denoted as (x,y,z)_(i).

FIG. 3C schematically illustrates instantaneous (x; y; z)_(i) values ofingestible device 12, as obtained with receivers 40 _(A), 40 _(B), and40 _(C). Based on theses values, an estimated distance L that has beentraveled by ingestible device 12, from intracorporeal reference systemu; v; w to site 82 may be calculated, by summing over estimatedincremental distances ΔL, as follows:L=ΣΔL, where ΔL=[(x _(i+1) −x _(i))²+(y _(i+1) −y _(i))²+(z _(i+1) −z_(i))²]^(1/2)

Preferably, the instantaneous values of (x; y; z)_(i) are obtained atvery short time intervals, for example, of a few seconds.

FIG. 3D schematically illustrates estimated distance L as a function oftime, since ingestion. Alternatively, another time may be used, forexample, the time from intracorporeal reference system u; v; w. Thus, asurgeon may observe, for example, that at 640 minutes after ingestion,which may correspond, for example, to 240 minutes from intracorporealreference system u; v; w, ingestible device 12 passed near site 82,having traveled approximately 2.8 meters within gastrointestinal tract14.

Thus, a diagnostic image of nuclear radiation may comprise diagnosticinformation as a function of time, as seen in FIG. 3A, or diagnosticinformation as a function of distance traveled by ingestible device 12,based on the information seen in FIG. 3D.

With reference to FIGS. 3A-3D, it will be appreciated that computerstation 20 (FIG. 1B) may be used in tandem with, or in place of computermeans 30 (FIG. 1C).

Referring further to the drawings, FIGS. 4A-4D schematically illustrateingestible device 12, arranged for imaging nuclear radiation of at leasttwo radioisotopes, and a method of imaging thereof, in accordance withanother preferred embodiment of the present invention.

The clock-like property of radioisotopes may by itself serve fortechniques to identify pathological sites in the body, as follows:

In a stagnant pool, the time-dependent isotope concentration N(t) of anisotope having an initial concentration N₀ and a decay constant λ may bedescribed as,N(t)=N ₀ e ^(−λt).

In the body, cleansing may be described by a cleansing rate constant φ.Thus, the time-dependent isotope concentration in the body decreases bydecay and cleansing, at a rate constant of λ+φ. Except where φ>>λ, thedecrease rate constant λ+φ is unique to each isotope.

At a pathological site, while buildup occurs by absorption, removaltakes place by decay and release, wherein release may be described by arelease rate constant η. Thus, the time-dependent isotope concentrationat the pathological site decreases at a rate constant of λ+η. As in thecase of the body in general, except where η>>λ, the decrease rateconstant λ+η is unique to each isotope.

In essence, a given isotope behaves as if it has different effectivedecay constants, as follows: λ+φ for the body in general, and λ+η forthe pathological site. Since the antibody or radiopharmaceutical isselected specifically because of a hold up mechanism within pathologies,which is markedly different from that of the tissue in general (i.e.,η<<φ), these effective decay constants may be used to identify apathological site.

A first technique to identify a pathological site is based onadministrating a radiopharmaceutical which contains two radio-isotopes,A and B, preferably bound to the same antibody. Within the body, thetime-dependent concentration of the two radio-isotopes will decrease atthe rates, λ_(A)+φ and λ_(B)+φ for A and B, respectively, and atime-dependent concentration ratio of A/B will depend on these values.However, at a pathological site, their time-dependent concentrationswill decrease at the rates, λ_(A)+η and λ_(B)+η for A and B,respectively. Thus, a change in the isotopic concentration ratio mayoccur at a pathological site. The change will be observed by a change inthe activity ratio between the tissue in general and the pathologicalsite.

In FIGS. 4A-4D, the administration of radiopharmaceutical to body 16 hasincluded a cocktail of two isotopes, I¹³¹ and I¹³³. Additionally,nuclear-radiation detector 49 has been arranged to distinguish betweenphotons of a first energy, associated with I¹³¹ and photons of a secondenergy, associated with I¹³³, based on the current pulses that aregenerated, as has been described hereinabove.

As seen in FIG. 4A, a pathological site 92 may exist in gastrointestinaltract 14, for example, at about 540 minutes from the time of ingestionof ingestible device 12. Additionally, as seen in FIGS. 4B and 4C,pathological site 92 is too small to generate statistically significantphoton peaks of radiation counts either of I¹³¹ or of I¹³³.

However, as seen in FIG. 4D, a change in the isotopic activity ratio,I¹³¹ to I¹³³, at site 92, is indicative of a suspected pathology.

It will be appreciated that a change in the isotopic activity ratio maybe observed even when statistically significant peaks ofnuclear-radiation counts are observed, and may be used as aconfirmation.

A diagnostic image of the change in the isotopic activity ratio maycomprise diagnostic information as a function of time, as seen in FIG.4D, or diagnostic information as a function of distance traveled byingestible device 12, based on the information seen in FIG. 3D.

A second technique to identify a pathological site is based onadministrating a radiopharmaceutical which contains two radio-isotopes,A and B, wherein only A is bound to an antibody. For the body ingeneral, the time-dependent concentration of the two radio-isotopes willdecrease at the rates, λ_(A)+φ and λ_(B)+φ for A and B, respectively,and the time-dependent concentration ratio of A/B will depend on thesevalues. However, at a pathological site, the time-dependentconcentration of A will decrease at the rate, λ_(A)+η, while that of Bwill decrease at the rate λ_(B)+φ, and the time-dependent concentrationratio of A/B at the pathological site will depend on these values.Again, a change in the isotopic activity ratio may be observed near apathological site.

In accordance with the present invention, the techniques for detecting apathological site, using activity ratios of two isotopes may beoptimized by the selection of isotopes, antibodies, the form ofadministration and the waiting period between the administration of theradiopharmaceutical and the ingestion of ingestible device 12.Additionally, three or more radio-isotopes may be used. Furthermore, theisotopes need not be chemically identical. Additionally, they need notbe bound to the same antibody. Many variations of the aforementionedtechniques, that rely on the clock-like property of radio-isotopes toidentify the hold-up mechanism, associated with a pathological site arepossible, and are within the scope of the present invention.

In accordance with the present invention, nuclear-radiation detector 49may include features taught by U.S. Pat. No. 4,801,803 to Denen, et al.,entitled, “Detector and localizer for low energy radiation emissions,”U.S. Pat. No. 5,151,598 to Denen, entitled, “Detector and localizer forlow energy radiation emissions,” U.S. Pat. No. 4,893,013 to Denen etal., entitled, entitled “Detector and Localizer for Low Energy RadiationEmissions,” and U.S. Pat. No. 5,070,878 to Denen, entitled, “Detectorand localizer for low energy radiation emissions,” and U.S. Pat. No.6,259,095, to Boutun, et al., entitled, “System and apparatus fordetecting and locating sources of radiation,” whose disclosures areincorporated herein by reference.

Referring further to the drawings, FIG. 5 schematically illustratesingestible device 12, arranged for indirect imaging of nuclear radiationby the scintillation that it produces, in accordance with still anotherpreferred embodiment of the present invention. The present embodimentprovides a technique for identifying a pathological site indirectly,with a scintillation liquid. Accordingly, probe 50 of ingestible device12 includes a photodetector 51. Ingestible device 12 may further includetransmitter 54, power source 52 and related circuitry 56, as has beendescribed hereinabove, in conjunction with FIG. 2A.

In accordance with the present embodiment, the administration ofpharmaceuticals to body 16 (FIG. 1A) includes a radiopharmaceutical anda scintillation liquid. White the radiopharmaceutical is administered,preferably, by injection, between several hours to about two days priorto the ingestion of ingestible device 12, the scintillation liquid ispreferably administered orally, about two hours prior to the ingestionof ingestible device 12.

Preferably, prior to the ingestion of ingestible device 12, body 16 isprepared so that minimal content is present in gastrointestinal tract14.

The scintillation liquid may be obtained, for example, from IN/U.S.Systems, Inc., 5809 North 50th Street, Tampa, Fla. 33610-4809, whichoffers two biodegradable, non-toxic scintillation cocktails, IN-FLOW BDand IN-FLOW ES. Both products have low viscosity to assure pumpability,are non-hazardous and can be disposed of as normal liquid waste.

As ingestible device 12 travels within gastrointestinal tract 14, it issurrounded by a scintillation liquid 94, which produces scintillation togamma and beta radiation. In the vicinity of pathological site 82,scintillation 96 is produced within the liquid, generated by nuclearradiation 81 from the radiopharmaceutical bound to site 82.Scintillation 96 will be detected by photodetector 51, and transmittedto apparatus 18, via transmitter 54.

A diagnostic image of scintillation may comprise diagnostic informationas a function of time, in a manner analogous to that seen in FIG. 3A, ordiagnostic information as a function of distance traveled by ingestibledevice 12, based on the information seen in FIG. 3D.

Photodetector 51 may comprise a single photo-sensing diode, or two ormore photo-sensing diodes. Examples of photo-sensing diodes that may beused for the present embodiment, include NT55-754 or NT53-372 describedin www.edmundoptics.com/IOD/DisplayProduct.cfm?productid=2232, of EdmundIndustrial Optics.

Referring further to the drawings, FIG. 6 schematically illustratesingestible device 12, arranged for imaging optical fluorescence, inaccordance with a preferred embodiment of the present invention. Theoptical fluorescence may be of a fluorescing-pharmaceutical, or of baregastrointestinal-tract tissue.

Preferably, probe 50 comprises a photodetector 55, similar, for example,to photodetector 51, described hereinabove, in conjunction with FIG. 5,but which preferably further includes a color filter, for example,NT46-149 obtained from Edmund Industrial Optics, hereinabove, so as tobe sensitive to a specific color. Alternatively, photodetector 51 maycomprise more than one photodiode, each having a different filter.

Additionally, ingestible device 12 further includes an excitation source78, preferably, a laser light source 78, distal to photodetector 55.Laser light source 78 may be fitted into ingestible device 12 as taughtby U.S. Pat. No. 6,324,418 Crowley, entitled, “Portable tissuespectroscopy apparatus and method,” whose disclosure is incorporatedherein by reference. A light barrier 79 may separate source 78 andphotodetector 55.

Ingestible device 12 may further include transmitter 54, power source 52and related circuitry 56, as has been described hereinabove, inconjunction with FIG. 2A.

A diagnostic image of optical fluorescence may comprise diagnosticinformation as a function of time, in a manner analogous to that seen inFIG. 3A, or diagnostic information as a function of distance traveled byingestible device 12, based on the information seen in FIG. 3D.

Known fluorescing pharmaceuticals, which give well structuredfluorescence spectra include hematoporphyrin derivatives (HPD), whenexcited in the Soret band around 405 nm. Additionally, they includedihematoporphyrin ether/ester (DHE), hematoporphyrin (HP),polyhematoporphyrin ester (PHE), and tetrasulfonated phthalocyanine(TSPC), when irradiated at 337 nm, for example by an N₂ laser. Each ofthese, or a combination of these, or other knownfluorescing-pharmaceutical and various combinations thereof may be used,in accordance with the present invention.

As taught by U.S. Pat. No. 5,115,137, to Andersson-Engels, et al,entitled, “Diagnosis by means of fluorescent light emission fromtissue,” whose disclosure is incorporated herein by reference, thefluorescing-pharmaceutical may include tetrasulfonated phthalocyanine(TSPC), and source 78 may comprise an N₂ laser for irradiation at 337nm.

Alternatively, as taught by U.S. Pat. No. 4,336,809, to Clark entitled,“Human and animal tissue photoradiation system and method,” whosedisclosure is incorporated herein by reference, thefluorescing-pharmaceutical may include a hematoporphyrin orhematoporphyrin derivative, and source 78 may comprise a xenon ionlaser. According to Clark, xenon ion laser has a singly ionized lasingtransition in the red range, at a wavelength of about 627 nanometers,which approximately matches the red absorption peak of hematoporphyrin.Additionally, xenon ion laser has a group of doubly ionized lines atwavelengths of about 406, 421, 424, and 427 nanometers. Theseapproximately match the 407 nanometer blue absorption peak ofhematoporphyrin.

Alternatively, as taught by Clark hereinabove, the pharmaceuticals thatare administered may include a hematoporphyrin or hematoporphyrinderivative, and source 78 may be a krypton ion laser which has406.7/413.1 nanometer lines matching the 407 nanometer absorption peakof hematoporphyrin.

As ingestible device 12 travels within gastrointestinal tract 14, anoptical fluorescence image of the fluorescing-pharmaceutical may begenerated. The information of the fluorescence image may be recorded ina manner analogous to that described in conjunction with FIG. 3A.

It will be appreciated that other pharmaceuticals may be used, havingabsorption peaks that may be specifically matched by an appropriatelaser.

Unlike U.S. Pat. No. 6,324,418 to Crowley, hereinabove, which teaches aingestible pill for performing laser-excited optical fluorescence ofbare tissue, the present invention includes administrating afluorescence pharmaceutical and inducing it at an energy thatspecifically matches an absorption peak of the pharmaceutical.

However, in accordance with other preferred embodiments of the presentinvention, ingestible device 12 may be arranged for imaging opticalfluorescence of bare gastrointestinal-tract tissue.

Referring further to the drawings, FIG. 7 schematically illustratesingestible device 12, arranged for imaging infrared radiation of thegastrointestinal-tract tissue, by infrared thermography, in accordancewith a preferred embodiment of the present invention.

In the small intestine, ingestible device 12 is likely to make contactwith the walls of gastrointestinal tract 14. However, in the colon,contact with the walls is unlikely. Infrared thermography, whichmeasures thermal energy emitted from a surface without contact, andproduces a temperature image for analysis, is thus uniquely suitable foruse with ingestible device 12.

Preferably, probe 50 comprises an infrared thermography detector 61,formed as photodetector 51, described hereinabove, in conjunction withFIG. 5, which further includes an IR filer, for example, IR-NT54-518,obtained from Edmund Industrial Optics hereinabove. Alternatively,infrared thermography detector 61 may be formed of a singlephoto-sensing diode, or two or more photo-sensing diodes for IR such asEPD-740-0/1.0-IR selective photo diode, obtained from_ROITHNERLASERTECHNIK, A-1040 Vienna, Austria, Schoenbrunner Strasse.

Ingestible device 12 may further include transmitter 54, power source 52and related circuitry 56, as has been described hereinabove, inconjunction with FIG. 2A.

As ingestible device 12 travels within gastrointestinal tract 14, animage of tissue temperature may be obtained. A pathological site, suchas site 82 (FIG. 3A) is likely to be at higher temperature than thesurrounding tissue, and may thus produce a thermography peak, indicativeof pathology.

A diagnostic image of tissue temperature may comprise diagnosticinformation as a function of time, in a manner analogous to that seen inFIG. 3A, or diagnostic information as a function of distance traveled byingestible device 12, based on the information seen in FIG. 3D.

Referring further to the drawings, FIGS. 8A and 8B schematicallyillustrate ingestible device 12, arranged for imagingtemperature-differences along the gastrointestinal-tract tissue, and amethod of imaging thereof, using at least one thermocouple 106 _(A), inaccordance with a preferred embodiment of the present invention.

A thermocouple is a known means for measuring temperature. It includestwo wires, made of different metals, connected at one end and veryclose, but not connected, at the other end. When the connected end ofthe thermocouple is placed in an area of higher temperature than theother end, a voltage builds up between the wires, at the other end.

At least one thermocouple probe 106 _(A) has tips 108 _(A1) and 108_(A2) which preferably are butt with the external surface of shell 58.Temperature differences may thus be measured between tips 108 _(A1) and108 _(A2). Preferably probe 50 includes additional thermocouples, suchas 106 _(B), having tips 108 _(B1) and 108 _(B2), and 106 _(C), havingtips 108 _(C1) and 108 _(C2). Ingestible device 12 may further includetransmitter 54, power source 52 and related circuitry 56, as has beendescribed hereinabove, in conjunction with FIG. 2A.

In the small intestine, direct contact between ingestible device 12 andthe walls of gastrointestinal tract 14 is likely to occur. As ingestibledevice 12 travels within gastrointestinal tract 14, particularly in thesmall intestine, differences in tissue temperatures are detected, astips 108 _(A), 108 _(B), and 108 _(C) form contact with tissue ofgastrointestinal tract 14. At an interface between a healthy tissue anda pathology, for example, where tip 108 _(A1) is in contact with thepathology, and tip 108 _(A2) is in contact with a healthy tissue, aspike, indicative of a temperature gradient between the two types oftissue, may be observed.

A diagnostic image of tissue temperature differences may comprisediagnostic information as a function of time, in the manner seen in FIG.8B, or diagnostic information as a function of distance traveled byingestible device 12, based on the information seen in FIG. 3D.

Referring further to the drawings, FIGS. 9A and 9B schematicallyillustrate ingestible device 12, arranged for imaging impedance of thegastrointestinal-tract tissue, and a method of imaging thereof, using atleast one impedance probe 110 _(A), in accordance with a preferredembodiment of the present invention. Impedance imaging has been founduseful in detecting tumors and other pathologies.

At least one impedance probe 110 _(A) has tips 112 _(A1) and 112 _(A2)which preferably are butt with the external surface of shell 58, so asto form direct contact with tissue of gastrointestinal tract 14.Preferably, tips 112 _(A1) and 112 _(A2) are formed of a biocompatiblemetal, such as SS, titanium, titanium alloy, and the like, or of anotherbiocompatible conductor. Impedance may thus be measured between tips 112_(A1) and 112 _(A2). Preferably probe 50 includes additional impedanceprobes, such as 110 _(B), having tips 112 _(B1) and 112 _(B2), and 110_(C), having tips 112 _(C1) and 112 _(C2).

Ingestible device 12 may further include transmitter 54, power source 52and related circuitry 56, as has been described hereinabove, inconjunction with FIG. 2A.

In the small intestine, direct contact between ingestible device 12 andthe walls of gastrointestinal tract 14 is likely to occur. As ingestibledevice 12 travels within gastrointestinal tract 14, particularly in thesmall intestine, differences in tissue impedance are detected, as tips112 _(A1) and 112 _(A2), 112 _(B1) and 112 _(B2), and 112 _(C1) and 112_(C2) form contact with tissue of gastrointestinal tract 14. Atpathological site, a change in impedance is likely to be observed.

A diagnostic image of tissue impedance may comprise diagnosticinformation as a function of time, in the manner seen in FIG. 9B, ordiagnostic information as a function of distance traveled by ingestibledevice 12, based on the information seen in FIG. 3D.

Referring further to the drawings, FIGS. 10A and 10B schematicallyillustrate additional components of ingestible device 12, in accordancewith other preferred embodiments of the present invention. Ingestibledevice 12 may further include any one of the following components:

-   i. a tracking system 48;-   ii. computer means 64, which may include a processor 66, and    preferably also a memory 68, for example, in a form of a    microcomputer 64;-   iii. a receiver 70, for receiving instructions from computer means    30 or from computer system 20, as will be described hereinbelow;-   iv. a transducer 69, in power communication with power source 52,    for extracorporeally energizing power source 52;-   v. circuitry and components 74 dedicated to signal amplification and    (or) preamplification, as known; and-   vi. circuitry and components 76, dedicated to reducing signal to    noise ratio, as known.

In accordance with the present invention, computer means 64 is anothercomponent of data-handling apparatus 53, arranged for receiving andhandling imaging data generated by probe 50. Computer means 64 may beused in tandem with computer means 30 of extracorporeal apparatus 18(FIG. 1C), and (or) computer station 20 (FIG. 1B), via transmitter 54,and possibly also, receiver 70, shown in FIG. 10A.

Alternatively, computer means 64 may be used in tandem with computermeans 30 of extracorporeal apparatus 18 (FIG. 1C), and (or) computerstation 20 (FIG. 1B), via receiver 70 only.

Alternatively, computer means 64 may be used in place of computer means30 of extracorporeal apparatus 18 (FIG. 1C) and in place of transmitter54, making ingestible device 12 an autonomous unit, as shown in FIG.10B. Accordingly, extracorporeal apparatus 18 need not be used.Preferably, where extracorporeal apparatus 18 is not used, data may berecorded by computer means 64, and retrieved with ingestible device 12after the completion of the diagnostic route in gastrointestinal tract14. Computer means 64 may record the data and perform calculations inmanners analogous to that of computer means 30 (FIG. 1C), or computerstation 20 (FIG. 1B), as described hereinabove, in conjunction withFIGS. 3A-9B. Memory 68 is preferably analogous to removable data storageimplement 38 (FIG. 1C) and may be removed and read by data readingimplement 44 of computer station 20 (FIG. 1B).

Power source 52 may be an energizable power source, which furtherincludes transducer 69, for example, as taught by U.S. Pat. No.6,277,078, to Porat, et al., entitled, “System and method for monitoringa parameter associated with the performance of a heart,” whosedisclosure is incorporated herein by reference. Preferably, transducer69 is a piezoelectric transducer, which may be energized byextracorporeal ultrasound radiation, directed at it.

Receiver 70 may be arranged for RF communication, which may bemultichanneled. Alternatively, receiver 70 may be an ultrasoundreceiver. Receiver 70 and transmitter 54 may be integrated to a singleunit.

Communication between the components of ingestible device 12 may bewired or wireless.

Various types of tracking systems 48 may be used, in accordance with thepresent invention. These may be additional to, or in place of pluralityof receivers 40 of extracorporeal apparatus 18 (FIG. 1C) and transmitter54, as will be described hereinbelow, in conjunction with FIGS. 13A-19B.

Referring further to the drawings, FIG. 11 schematically illustratesingestible device 12, arranged for imaging ultrasound reflection of thegastrointestinal-tract tissue, in accordance with a preferred embodimentof the present invention. Accordingly, probe 50 comprises an ultrasoundprobe 67, formed, for example, as a transducer array, arranged fortransmitting and receiving the ultrasonic radiation. Ingestible device12 may further include computer means 64, and (or) transmitter 54 andpossibly also receiver 70, and other components, as describedhereinabove, in conjunction with FIGS. 10A and 10B.

Ultrasound probes similar to probe 67 of the present invention aretaught by U.S. Pat. No. 5,088,500 to Wedel, et al., entitled,“Ultrasound finger probe and method for use,” U.S. Pat. No. 5,284,147,to Hanoaka, et al., entitled, “Ultrasonic probe to be installed onfingertip,” and U.S. Patent Application 20010020131, to Kawagishi,Tetsuya, et al., entitled, “Ultrasonic diagnosis system,” whosedisclosures are incorporated herein by reference.

Various contrast agents may be used with ultrasound probe 67, forexample, as taught by U.S. Pat. No. 6,280,704, to Schutt, et al.,entitled, “Ultrasonic imaging system utilizing a long-persistencecontrast agent,” whose disclosure is incorporated herein by reference.

A diagnostic image of ultrasound reflection may comprise diagnosticinformation as a function of time, in the manner analogous to that seenin FIG. 3A, or diagnostic information as a function of distance traveledby ingestible device 12, based on the information seen in FIG. 3D.

Referring further to the drawings, FIGS. 12A-12C schematicallyillustrate ingestible device 12, arranged for imaging magnetic resonanceof the gastrointestinal-tract tissue, in accordance with a preferredembodiment of the present invention. Accordingly, probe 50 comprises anMRI probe 63.

MRI probe 63 comprises a miniature permanent magnet 120, preferablyformed as a cylindrical rod. Permanent magnet 120 defines a longitudinalaxis z, and has magnetic field B₀ in the z direction. Additionally, MRIprobe 63 comprises an RF coil 122, preferably surrounding permanentmagnet 120. RF coil 122 may be formed as a bird cage RF coil.Alternatively, RF coil may be formed as a multiple-turn RF coil, themultiple turns surrounding permanent magnet 120. Alternatively, anotherknown RF coil may be used.

In accordance with a preferred embodiment of the present invention, nogradient coils are used; positional information may be acquired, as hasbeen described hereinbelow, in conjunction with FIGS. 3A-3D, or asdescribed hereinabove, in conjunction with FIGS. 13A-17B.

Thus, a diagnostic image of MRI may comprise diagnostic information as afunction of time, in the manner analogous to that seen in FIG. 3A, ordiagnostic information as a function of distance traveled by ingestibledevice 12, based on the information seen in FIG. 3D.

In accordance with another preferred embodiment of the presentinvention, gradient coils 124, formed for example, as antihelmholtz typeof coils may be used.

The operation of MRI Probe 63 may be controlled by computer station 20,or by computer means 30, in a wireless manner, via receiver 70.Alternatively, the operation of MRI probe 63 may be controlled bycomputer means 64.

In accordance with a preferred embodiment of the present invention, foruse with MRI probe 63, transmitter 54 preferably comprises an ultrasoundtransmitter, and receiver 70 preferably comprises an ultrasoundreceiver, wherein the transmitter and receiver may be incorporated intoa single ultrasound transducer. Thus, interference from extraneous RFsignals is minimized.

Various contrast agents may be used with MRI probe 63, for example, astaught by U.S. Pat. No. 6,315,981 to Unger, entitled, “Gas filledmicrospheres as magnetic resonance imaging contrast agents,” whosedisclosure is incorporated herein by reference.

Referring further to the drawings, FIGS. 13A-13B schematicallyillustrate tracking system 48, using at least one acceleration sensor152, in accordance with a preferred embodiment of the present invention.

As seen in FIG. 13A, tracking system 48 may comprise at least oneacceleration sensor 152, which senses accelerations in at least threedegrees of freedom, such as with respect to a set of three mutuallyperpendicular coordinate axes. Alternatively, tracking system 48 maycomprise at least three acceleration sensors 152, each sensingaccelerations along a single axis of a set of three mutuallyperpendicular coordinate axes. The acceleration sensors may comprise oneor more miniature or micro-accelerometers. Computer means 64 or computermeans 30 may estimate distance L (FIG. 3A) traveled by gastrointestinaldiagnostic device 12, within gastrointestinal tract 14, as a function ofan accelerations sensed by the acceleration sensors.

As seen in FIG. 13B, extracorporeal apparatus 18 may further include atleast one extracorporeal acceleration sensor 154 which sensesaccelerations in at least three degrees of freedom, or at least threeacceleration sensors, each sensing accelerations in a single degree offreedom, of the set of three mutually perpendicular coordinate axes. Inthis way, correction for the motion of body 16 (FIG. 1A) may be made.

Acceleration sensors 152 and 154 may be used in place of plurality ofantennae 40, or in addition to them.

Referring further to the drawings, FIGS. 14A-14C schematicallyillustrate tracking system 48, by magnetic tracking and location, inaccordance with another preferred embodiment of the present invention.Tracking system 48 may comprise a system 158 known as miniBird™, whichis a magnetic tracking and location system commercially available fromAscension Technology Corporation, P.O. Box 527, Burlington, Vt. 05402USA. The miniBird™ 158 measures the real-time position and orientation(six degrees of freedom) of one or more miniaturized sensors, so as toaccurately track the spatial location of probes, instruments, and otherdevices. Thus, distance L (FIG. 3A) may be estimated. The dimensions ofminiBird™ 158 are 18 mm×8 mm×8 mm for Model 800 and 10 mm×5 mm×5 mm theModel 500, small enough for use with ingestible device 12.

Experimental results of the operation of miniBird™ 158 are seen in FIGS.14B and 14C. A flexible U-shaped plastic tube 140, of 120 cm in lengthand 6 cm in diameter, was fixed to a flat surface (not shown) and servedas a model for the human colon. A single radiation source constituting apoint source 142 of 100 μCi of ⁵⁷Co was attached to the outer surface ofthe tube. Ingestible device 12, was simulated by radiation detector 144comprising a 125 mm³ CdZnTe crystal, obtained from eV Products, PA, USA)375 Saxonburg Blvd. Saxonburg, Pa. 16056, used without a collimator.

Attached to radiation detector 144 was miniBird 158, forming a model ofingestible device 12. The count readings were filtered using an energywindow of +/−6% around the 122 KeV energy peak. Radiation detector 144and miniBird 158 were tied to a string (not shown) and pulled by hand, adistance L′ through the lumen of tube 140, past radiation source 142.The integrated count readings and location information were relayed to apersonal computer for processing and visual presentation. The end resultwas a color-coded map, shown in black-and-white in FIG. 14C, which wasproportional to the radiation count readings detected along the tube.FIG. 14C shows a gradual increase in radiation and a gradual declinewith peak radiation corresponding to the true location of the source.

The result confirms that ingestible device 12, equipped with a radiationdetector and location system and software may correctly identify aradiolabeled tissue within the gastrointestinal tract.

Referring further to the drawings, FIG. 15 schematically illustrates atracking system 48, which includes at least one miniature roller 84, inaccordance with yet another embodiment of the present invention.Accordingly, ingestible device 12 further includes at least oneminiature roller 84, external to shell 58. Roller 84 is in communicationwith a counter 86, which is internal to shell 58 and which countscomplete revolutions performed by roller 84 and converts the count tosignals, which are relayed to transmitter 54 and transmitted toextracorporeal computer means 30. Roller 84 measures distance traveledby ingestible device 12 in a manner similar to that by which tiresmeasure the distance traveled by a car. In some embodiments, two or morerollers 84 may be used.

Preferably, ingestible device 12 with at least one roller 84 areenclosed within a cast 88 of gelatin, sugar or another substance thatdissolves easily, to facilitate swallowing. In stomach 11 (FIG. 1A) cast88 dissolves, uncovering at least one roller 84, which may then trackthe distance traveled in gastrointestinal tract 14, from intracorporealreference system u; v; w, at the exit of stomach 11. The distancetraveled by ingestible device 12, may be presented as a function oftime, in a manner analogous to that of FIG. 3D.

Referring further to the drawings, FIGS. 16A-16B schematicallyillustrate tracking system 48, which is based on cross correlation ofreflected light, in accordance with still another preferred embodimentof the present invention.

Cross correlation of reflected light is a technique of movementtracking, used by Logitec iFeel™ MouseMan.

As seen in FIG. 16A, tracking system 48 comprises a light source 75, forexample, a light-emitting diode 75, and at least two photo-sensingdiodes, 71 _(A) and 71 _(B), arranged a distance Δ

□ □ □ □

□ □ □ □

□ □

□ □ □ □ □ Preferably, a light barrier 79 separates light-emitting diode75 and photo-sensing diodes, 71 _(A) and 71 _(B).

Light, emitted from diode 75, is reflected by the walls ofgastrointestinal tract 14 and detected by the at least two photo-sensingdiodes, 71 _(A) and 71 _(B). By cross correlating detected signals at afirst time T and at a later time T+ΔT, the incremental distance traveledby ingestible device 12, within gastrointestinal tract 14, during periodΔT may be evaluated. Distance L (FIG. 3A), traveled by ingestible device12, may thus be evaluated by summing the incremental distances.Preferably, period ΔT is of the order of several seconds.

Alternatively, as seen in FIG. 16B, a photodetector 71, comprising aplurality of photo-sensing diodes, may be used, arranged with variousdistances between them along the R axis, to enhance the crosscorrelation.

In embodiments where light source 78 (FIG. 6) is used, as describedhereinabove, light source 78 may be used in place of diode 75.

Additionally, photo-sensing diodes, 71 _(A) and 71 _(B) may be arrangedto sense reflected light, emitted by light source 75 or 78, or opticalfluorescence.

In accordance with the present invention, other forms of crosscorrelation may be used, for example, by ultrasound reflection, nuclearradiation, infrared radiation, scintillation produced by a scintillationliquid, impedance measurements, and the like.

Referring further to the drawings, FIG. 17 schematically illustratestracking system 48, wherein cross correlation is based onbackground-level nuclear radiation, in accordance with still anotherpreferred embodiment of the present invention. Accordingly,nuclear-detector 49 includes at least two, and preferably a plurality ofcrystals, arranged with various distances between them along the R axis.By cross correlating background radiation levels at a first time T andat a later time T+ΔT, the incremental distance traveled by ingestibledevice 12 during period ΔT may be evaluated.

Referring further to the drawings, FIG. 18 schematically illustratestracking system 48, wherein cross correlation is based on infraredradiation, in accordance with yet another preferred embodiment of thepresent invention. Thus, thermography detector 61 may comprise at leasttwo, and preferably a plurality of photo-sensing diodes, arranged withvarious distances between them along the R axis. By cross correlatinginfrared radiation levels at a first time T and at a later time T+ΔT,the incremental distance traveled by ingestible device 12 during periodΔT may be evaluated.

Similarly, tracking in the small intestine may be performed by crosscorrelation of impedance, using an impedance probe, which is preferablya multi-element impedance probe, with the multi-elements arranged withvarious distances between them, along the R axis, in accordance withstill another preferred embodiment of the present invention.

Additionally, tracking in the small intestine may be performed by crosscorrelation of temperature differences, using a thermocouple probe,which is preferably a multi-element thermocouple probe, with themulti-elements arranged with various distances between them, along the Raxis, in accordance with yet another preferred embodiment of the presentinvention.

Referring further to the drawings, FIGS. 19A and 19B schematicallyillustrates tracking system 48, using ultrasound radiation, inaccordance with still other preferred embodiments of the presentinvention. Tracking system 48 comprises a piezoelectric transducer 72,operable in the frequency range of about 40 KHz to about 20 MHz, at apower of few milliwatts.

Piezoelectric transducer 72 is operable by several methods, for trackingingestible device 12, as follows:

-   1. Tracking may be performed by cross correlation of ultrasound    radiation. As seen in FIG. 19A, a signal sent by transducer 72 will    be reflected off the walls of gastrointestinal tract 14, and    received again by transducer 72 and at least one additional    transducer 77, of similar characteristics. Transducers 77 and 72 are    arranged at a predetermined distance between them, along the R axis.    By cross correlating signals from transducer 72 at a first time T    and at a later time T+ΔT, the incremental distance traveled by    ingestible device 12 during period ΔT may be evaluated.    Additionally, a plurality of transducers 77 may be used, arranged    with various distances between them, along the R axis.-   2. Transducer 72 may operate in tandem with at least three    extracorporeal receivers 40 _(A), 40 _(B) and 40 _(C) (FIG. 1C),    formed as piezoelectric transducers and arranged in direct contact    with body 16, at different locations. For example, extracorporeal    transducers 40 _(A), 40 _(B) and 40 _(C) may be patch-sensor    devices, described in U.S. Pat. Nos. 5,807,268; 5,913,829 and    5,885,222, all of which are assigned to MedAcoustics, Inc., Raleigh,    N.C., USA, the disclosures of which are incorporated herein by    reference. A first signal, sent by transducer 40 _(A) is received by    transducer 72, then sent out again by transducer 72 and received by    transducers 40 _(A), 40 _(B) and 40 _(C). A second signal, sent by    transducer 40 _(B) is received by transducer 72, then sent out again    by transducer 72 and received by transducers 40 _(A), 40 _(B) and 40    _(C). A third signal, sent by transducer 40 _(C) is received by    transducer 72, then sent out again by transducer 72 and received by    transducers 40 _(A), 40 _(B) and 40 _(C). A signal is then sent out    again by transducer 40 _(A) and the process is repeated. The    distance between transducers 40 _(A) and 72 is calculated based on    the time the signal traveled from transducer 40 _(A) to transducer    72 and back to transducer 40 _(A). In a similar manner, the    distances between transducers 40 _(B) and 72 and between transducers    40 _(C) and 72 may be calculated. As a result, the instantaneous x;    y; z location of ingestible device 12 may be obtained, and distance    L (FIG. 3A) traveled by ingestible device 12, may be estimated, as    described hereinbelow, in conjunction with FIGS. 3C and 3D.    Additional extracorporeal transducers, such as 40 _(D), 40 _(E), and    40 _(F), may further be used.-   3. Alternatively, or additionally, signals sent by transducer 72 may    be received by at least three extracorporeal transducers 40 _(A), 40    _(B) and 40 _(C), and the distances from receivers 40 to transducer    72 may be estimated in accordance with the inverse square    relationship, based on differences in amplitudes.

Transducer 72 may further be used as an ultrasound transmitter, in placeof, or in addition to transmitter 54 (FIG. 2A). Furthermore, transducer72 may be used as an ultrasound receiver, in place of, or in addition toreceiver 70 (FIG. 10A). As such, transducer 72 comprises data-handlingapparatus 53 and is arranged for receiving and handling imaging datagenerated by probe 50.

It is important to point out the difference in approach, betweenestimating distance L (FIG. 3A), as described hereinabove, inconjunction with FIGS. 3C-3D, 13A-13B, 14A-14C and 19B, and evaluatingdistance L, as described hereinabove, in conjunction with FIGS. 15, 16A,16B, 17, 18, and 19A.

In FIGS. 3C-3D, 13A-13C, 14A-14C, and 19B, instantaneous x; y; z, valuesare obtained with respect to extracorporeal reference system x; y; z,using at least three extracorporeal receivers, or at least oneacceleration sensor, or a magnetic tracking and location system. Thisapproach is fraught with a small error due to movement ofgastrointestinal tract 14, as part of the digestive process. Thus, acalculation of the distance traveled by ingestible device 12, forexample, from the exit of stomach 11 to a pathological site, will, giveonly an estimated distance.

Yet, in FIGS. 15, 16A, 16B, 17, 18, and 19A, incremental distances areobtained vis a vis the walls of gastrointestinal tract 14, using aroller or cross correlation of a sensed parameter. This approach is freeof any error due to movement of gastrointestinal tract 14. Thus, acalculation of the distance traveled by ingestible device 12 will give amore exact value, than that of the first approach.

The present invention further includes a gastrointestinal-tractdiagnostic program, comprising a range of ingestible devices, suitablefor general screening of a large population, on the one hand, andspecific diagnoses of suspected pathologies, on the other.

For example, general screening for gastrointestinal-tract neoplasm maybe addressed with ingestible device 12, comprising nuclear-radiationdetector 49, ingested after the administration of an anti-CEA oranti-TAG-72 radiopharmaceutical, or a radiopharmaceutical containingboth.

Specific diagnoses, for example, of inflammations, may be addressed withingestible device 12, comprising nuclear-radiation detector 49, ingestedafter the administration of Ga⁶⁷ citrate which is used for the detectionof chronic inflammation, or after the administration of Tc^(99m)-HMPAOleukocytes, which have high sensitivity and specificity for acuteinfections.

It will be appreciated that many other combinations of ingestible device12 and a specific pharmaceutical may be employed.

In accordance with another preferred embodiment of the presentinvention, general screening for gastrointestinal-tract pathologies maybe addressed without a pharmaceutical Additionally, general screeningmay be addressed by providing an inexpensive ingestible device, whichneed not be retrieved and may be disposed of naturally, by the body. Itmay be pointed out that for general screening, ingestible device 12 thatneed not be retrieved is advantageous, since invariably, retrieval isassociated with psychological and physical uncasiness.

An example of a relatively inexpensive ingestible device 12, operativewithout a pharmaceutical, is provided by ingestible device 12 of FIG. 7,hereinabove, wherein infrared thermography detector 61 is used fortemperature imaging. Additionally, an example is provided in FIG. 8A,hereinabove, wherein at least one thermocouple probe 106 _(A) is used,for temperature-difference imaging, particularly of the small intestine.Additionally, an example is provided in FIG. 9A, hereinabove, wherein atleast one impedance probe 110 _(A) is used, for impedance imaging,particularly of the small intestine. These may be used alone, or incombination. Since these are used without pharmaceuticals, there arelittle side effects associated with them.

Referring further to the drawings, FIG. 20 schematically illustrates apreferably disposable general-screening ingestible device 12, inaccordance with a preferred embodiment of the present invention.Preferably, ingestible device 12 includes infrared thermography detector61, for temperature imaging without contact Furthermore, infraredthermography detector 61 preferably includes a plurality ofphoto-sensing diodes, arranged, for example, along the R axis, fortracking ingestible device 12 by cross correlation of infraredradiation.

Additionally, general-screening ingestible device 12 may include amulti-element thermocouple probe 106, having a plurality of tips 108 ₁and 108 ₂, arranged, for example, as two or more rings around thecircumference of ingestible device 12. Furthermore, general-screeningingestible device 12 may include a multi-element impedance probe 110,having a plurality of tips 112 ₁, and 112 ₂, 108 ₂, arranged, forexample, as two or more rings around the circumference of ingestibledevice 12.

While multi-element thermocouple probe 106 and impedance probe 110 aresuitable for diagnosis of the small intestine, infrared thermographydetector 61 is arranged to produce a temperature image of entiregastrointestinal tract 14.

Preferably, ingestible device 12 further includes power source 52,transmitter 54 or transducer 72 (FIG. 19B) and related circuitry 56.

In accordance with the present invention, general screening ingestibledevice 12 may be administered as a first stage. Where pathologies aresuspected, imaging may be repeated with ingestible device 12 arrangedfor other forms of diagnosis, preferably with specific pharmaceuticals.

Additionally, ingestible device 12, arranged for other forms ofdiagnosis may further include the probes of general screening ingestibledevice 12, in order to correlate early findings with those of laterstages.

In accordance with the present invention, ingestible device 12 maycomprise a single probe 50, or two or more different probes 50, forproducing simultaneous imaging by different techniques.

In accordance with the present invention, ingestible device 12 maycomprise probe 50 and a second probe, formed as a video camera, forexample, a video camera as taught by U.S. Pat. No. 5,604,531, to Iddan,et al., entitled, “In vivo video camera system,” and U.S. PatentApplication 20010035902, to Iddan, G. J., et al. entitled, “Device andsystem for in vivo imaging,” whose disclosures are incorporated hereinby reference.

In accordance with the present invention, the choice of aradiopharmaceutical for the detection of neoplastic tissue, may includeany one of the following

-   1. CEA-Scan is a Tc^(99m)-labeled monoclonal antibody fragment,    which targets CEA, or an anti-CEA monoclonal antibody labeled by    another radioisotope, for example, I¹³¹. (Jessup J M. 1998, Tumor    markers—prognostic and therapeutic implications for colorectal    carcinoma, Surgical Oncology; 7: 139-151.)-   2. In^(99m)-Satumomab Pendetide (Oncoscint®), as an anti TAG-72.    (Molinolo A; Simpson J F; et al. 1990, Enhanced tumor binding using    immunohistochemical analyses by second generation    anti-tumor-associated glycoprotein 72 monoclonal antibodies versus    monoclonal antibody B72.3 in human tissue, Cancer Res. 50(4):    1291-8.)-   3. Anti-Lipid-Associated Sialic Acid (LASA). (Ebril K M, Jones J D,    Klee G G. 1985, Use and limitations of serum total and lipid-bound    sialic acid concentrations as markers for Colorectal cancer, Cancer;    55:404-409.)-   4. Anti-Matrix Metaloproteinase-7 (MMP-7). (Mori M, Barnard G F et    al. 1995, Overexpression of matrix metalloproteinase-7 mRNA in human    colon carcinoma. Cancer; 75: 1516-1519.)

Additionally, in accordance with the present invention, aradiopharmaceutical may be used a marker for nonmalignant pathologies,such as gastrointestinal inflammations and infections. Examples includethe following:

-   1. Ga⁶⁷ citrate. (Mettler F A, and Guiberteau M J, Eds. 1998,    Inflammation and infection imaging. Essentials of nuclear medicine.    Fourth edition. Pgs: 387-403.)-   2. Nonspecific-polyclonal immunoglobulin G (IgG). (Mettler F A, and    Guiberteau M J, ibid.)-   3. Radio-labeled leukocytes, such as such as In¹¹¹ oxine leukocytes    and Tc^(99m) HMPAO leukocytes. (Mettler F A, and Guiberteau M J,    ibid; Corstens F H; van der Meer J W. 1999. Nuclear medicine's role    in infection and inflammation. Lancet; 354 (9180): 765-70.)

The particular choice of a radionuclide for labeling theradiopharmaceutical is dependent upon its nuclear properties, thephysical half-life, the detection instruments' capabilities, thepharmacokinetics of the radiolabeled antibody, and the degree ofdifficulty of the labeling procedure. The radionuclide may be, forexample, any one of Technetium Tc^(99m), Iodine I¹²⁵, I¹²³, I¹³¹, andI¹³³, Indium In¹¹¹, Gallium Ga⁶⁷, thallium Tl²⁰¹, fluorine F¹⁸ and P³².

Referring further to the drawings, FIG. 21 schematically illustratesingestible device 12, in accordance with a preferred embodiment of thepresent invention. For the purpose of illustration, ingestible device 12is shown in a coordinate system x; y; z. Preferably, probe 50 ofingestible device 12 includes a plurality of nuclear-radiation detectors49, such as nuclear radiation detectors 49(1), 49(2), 49(3), 49(4), . .. 49(n), which preferably cover up the external surface of ingestibledevice 12. Preferably, each detector 49(n) is operative as a singlepixel.

It will be appreciated that this design may also lend itself to aCompton camera, as some of detectors 49(n) are opposite each other.Thus, a few of detectors 49(n) may be dedicated for this purpose. Theshape of ingestible device 12 may then change slightly, for example,include a narrow portion, similar for example, to a Coke bottle, toallow the compton camera detectors to be closer to each other.

Preferably, radiation detectors 49 are room temperature, solid-statedetectors, preferably, CdZnTe, obtained, for example, from IMARADIMAGING SYSTEMS LTD., of Rehovot, ISRAEL, 76124. Alternatively, otherdetectors as known may be used, for example, solid state detectors, suchas CdTe, HgI, Si, Ge, and the like, and scintillation detectors, such asNaI(Tl), LSO, GSO, Csl, CaF, and the like.

Room temperature solid-state CdZnTe (CZT) is among the more promisingnuclear detectors currently available. It has a better count-ratecapability than other detectors on the market, and its pixilatedstructure provides intrinsic spatial resolution. Furthermore, because ofthe direct conversion of the gamma photon to charge-carriers, energyresolution is enhanced and there is better rejection of scatter eventsand improved contrast.

In accordance with the present invention, the detector may be optimized,in accordance with the teaching of “Electron lifetime determination insemiconductor gamma detector arrays,” “GdTe and CdZnTe Crystal Growthand Production of Gamma Radiation Detectors,” and “Driving EnergyResolution to the Noise Limit in Semiconductor Gamma Detector Arrays,”Poster presented at NSS2000 Conference, Lyon France, Oct. 15-20, 2000,all by Uri Lachish, of Guma Science, P.O. Box 2104, Rehovot 76120,Israel, all of whose disclosures are incorporated herein b) reference.

Accordingly, each radiation detector 49(n) may be a monolithic CdZnTecrystal, doped with a trivalent donor, such as indium. Alternatively,aluminum may be used as the trivalent donor. When a trivalent dopant,such as indium, replaces a bivalent cadmium atom within the crystallattice, the extra electron falls into a deep trap, leaving behind anionized shallow donor. The addition of more donors shifts the Fermilevel from below the trapping band to somewhere within it. An optimaldonor concentration is achieved when nearly all the deep traps becomeoccupied and the Fermi level shifts to just above the deep trappingband.

Optimal spectral resolution may be achieved by adjusting the gammacharge collection time (i.e., the shape time) with respect to theelectron transition time from contact to contact. Gamma photons areabsorbed at different depth within the detector where they generate theelectrons. As a result, these electrons travel a different distance tothe counter electrode and therefore produce a different external signalfor each gamma absorption event. By making the shape time shorter thanthe electron transition time, from contact to contact, these externalsignals become more or less equal leading to a dramatic improvement inresolution.

Furthermore, for a multi-pixel detector, the electrons move from thepoint of photon absorption towards the positive contact of a specificpixel. The holes, which are far slower, move towards the negativecontact, and their signal contribution is distributed over a number ofpixels. By adjusting the gamma charge collection time (i.e., the shapetime) with respect to the electron transition time from contact tocontact, the detector circuit collects only the electrons' contributionto the signal, and the spectral response is not deteriorated by thecharge of the holes.

For an optimal detector, crystal electrical resistively may be, forexample, about 5×10⁸ ohm cm. The bias voltage may be, for example, −200volts. The shape time may be, for example, 0.5×10⁻⁶ sec. It will beappreciated that other values, which may be larger or smaller are alsopossible.

Referring further to the drawings, FIG. 22 schematically illustrates adevice for detector 49(n) calibration in accordance with a preferredembodiment of the present invention. Non-uniformity of the materialleads to different sensitivities for each pixel 49(n), of probe 50. Acorrection is required to eliminate the sensitivity effect of thedifferent pixels.

The calibration procedure includes placing ingestible device 12 in acylindrical source 200, enclosed by cylindrical source walls 204 and topand bottom plate sources 202, and maintaining a substantially even flux206. Preferably the radiation that is used is low gamma radiation, forexample, 24 KeV.

Referring further to the drawings, FIG. 23 schematically illustrates amethod for detector calibration, in accordance with a preferredembodiment of the present invention. For each detector 49(n), thelocation of the energy peak, corresponding to the peak photon energy,for example, 24 KeV, is bounded, by an upper level (UL) and a lowerlevel (LL) for that detector, forming an energy window for the specificdetector 49(n). Only photons which fall within the bounded energy windoware counted, to exclude Compton scattering and pair production. Amulti-energy source may be used, and several energy windows may bebounded for each detector 49(n).

After the energy windows, representing specific energy peaks, aredetermined for each detector 49(n), they are stored in a memory unit.

To correct for the different sensitivities of each detector, due tonon-uniformity of the material, each detector 49(n) is assigned asensitivity correction factor f(n). To obtain f(n), the total counts ofingestible device 12 in a given period is divided by the number ofdetectors, or pixels 49(n), thus obtaining an average count per pixel.That average, divided by the actual counts of a particular detector,yields the correction factor f(n). For example,

${f(1)} = \frac{{average}\mspace{14mu}{count}\mspace{14mu}{per}\mspace{14mu}{pixel}}{{actual}\mspace{14mu}{counts}\mspace{14mu}{in}\mspace{14mu} 49\;(1)}$

During acquisition, the sum of counts within the bounded windows of eachdetector 49(n) is multiplied by the the correction factor f(n) to obtaina sensitivity corrected count rate.

It will be appreciated that image reconstruction analysis may includevarious deconvolution algorithms, as known, for example, as taught incommonly owned, concurrently filed, co-pending application, “RadioactiveEmission detector Equipped with a Position Tracking System,” whosedisclosure is incorporated herein by reference.

Referring further to the drawings, FIG. 24 schematically illustrates amethod of calculating the depth, d, of a radiation source 220, based onthe attenuation of photons of different energies, which are emitted fromthe same source 220, within tissue layer 212, by ingestible device 12,in accordance with a preferred embodiment of the present invention.

The transmitted intensity of a monochromatic gamma-ray beam of photonenergy E and intensity I₀ crossing a) absorbing layer, such as tissuelayer 212, of a depth d, is a function of the following: the photonsenergy E, the layer thickness d, and the total linear attenuationcoefficient as a function of energy, μ_(total), of the materialconstituting the layer. The transmitted intensity is given by:I(E)=I ₀(E)exp(−μ_(total)(E)d)  (Eq-1)

The linear attenuation coefficient is expressed in cm⁻¹ and is obtainedby multiplying the cross section (in cm²/gr) with the absorbing mediumdensity. The total linear attenuation coefficient accounts forabsorption due to all the relevant interaction mechanisms: photoelectriceffect, Compton scattering, and pair production.

The layer thickness d, which is the depth of the radiation source, canbe measured using a radionuclide that emits two or more photon energies,since attenuation is a function of the photon energy.

For photons of different energies, originating from a same source, andhaving the same half-life, we get:

$\begin{matrix}{\frac{I\left( E_{1} \right)}{I\left( E_{2} \right)} = {\frac{I_{0}\left( E_{1} \right)}{I_{0}\left( E_{2} \right)} \cdot \frac{{\mathbb{e}}^{{- {\mu{(E_{1})}}} \cdot d}}{{\mathbb{e}}^{{- {\mu{(E_{2})}}} \cdot d}}}} & \left( {{Eq}\text{-}2} \right) \\{A = {{{\frac{I\left( E_{1} \right)}{I\left( E_{2} \right)}\&}\mspace{14mu} B} = \frac{I_{0}\left( E_{1} \right)}{I_{0}\left( E_{2} \right)}}} & \left( {{Eq}\text{-}3} \right) \\{R = {\frac{A}{B} = \frac{\left\lbrack {{I\left( E_{1} \right)}/{I\left( E_{2} \right)}} \right\rbrack}{\left\lbrack {{I_{0}\left( E_{1} \right)}/{I_{0}\left( E_{2} \right)}} \right\rbrack}}} & \left( {{Eq}\text{-}4} \right) \\{A = {\left. {B \cdot \frac{{\mathbb{e}}^{{- {\mu{(E_{1})}}} \cdot d}}{{\mathbb{e}}^{{- {\mu{(E_{2})}}} \cdot d}}}\Rightarrow R \right. = \frac{{\mathbb{e}}^{{- {\mu{(E_{1})}}} \cdot d}}{{\mathbb{e}}^{{- {\mu{(E_{2})}}} \cdot d}}}} & \left( {{Eq}\text{-}5} \right)\end{matrix}$R=e ^({μ(R) ² ^()−μ(E) ¹ ^()}d)

ln(R)=[μ(E ₂)−μ(E ₁)]d  (Eq-6)

The source depth, d, can be calculated as:

$\begin{matrix}{d = {\frac{\ln(R)}{{\mu\left( E_{2} \right)} - {\mu\left( E_{1} \right)}} = \frac{\ln\left\{ {\left\lbrack {{I\left( E_{1} \right)}/{I\left( E_{2} \right)}} \right\rbrack/\left\lbrack {{I_{0}\left( E_{1} \right)}/{I_{0}\left( E_{2} \right)}} \right\rbrack} \right\}}{{\mu\left( E_{2} \right)} - {\mu\left( E_{1} \right)}}}} & \left( {{Eq}\text{-}7} \right)\end{matrix}$

The linear attenuation coefficients for specific energies are calculatedfrom the photon mass attenuation and energy absorption coefficientstable.

The ratio I₀(E₁)/I₀(E₂) for a known isotope or isotopes is calculatedfrom an isotope table and the ratio I(E₁)/I(E₂) is measured at theinspected object edges.

Additionally, X-ray information, for example, mammography may be used,for more material linear attenuation coefficient, since X-ray imagingprovides information about the material density.

For example, we may consider a lesion inside a soft tissue, such as abreast, at a distance d that holds an isotope of ¹²³I, which emits twomain photons, as follows:

-   -   E₁=27 keV with 86.5%; and    -   E₂=159 keV with 83.4%.

The soft tissue density is 0.8 g/cm³.

The linear attenuation coefficients for E₁ and E₂ are calculated from J.H Hubbell, “Photon Mass Attenuation and Energy—absorption Coefficientsfrom 1 keV to 20 MeV”. Int. J. Appl. Radiat Isat. Vol. 33. pp. 1269 to1290, 1982, as follows:μ(E ₁)=(0.474 cm/g→μ(E ₁)=0.474 cm/g·0.8 g/cm³=0.38 l/cmμ(E ₂)=0.1489 cm/g→μ(E ₂)=0.1489 cm/g·0.8 g/cm³=0.119 l/cm

The measured ratio between I(E₁) to I(E₂) on the attenuating soft tissueedge is 0.6153.

Using Eq-7, one gets that the lesion depth is: d=2 cm.

Alternatively, if the measured ration between I(E₁) to I(E₂) is 0.473the extracted lesion depth is; d=3 cm.

It will be appreciated that when two or more isotopes used for obtainingthe different photons, corrections for their respective half-lives maybe required.

It will be appreciated that by calculating the depth of a radiationsource at each position, one may obtain a radiation source depth map,with respect to the gastrointestinal, track, as ingestible device 12travels through it. This information may be superimposed on a radiationsource image, as produced by other methods. For example, a radiationsource image produced by deconvolution algorithms may be superimposed ona radiation source image produced by depth calculations, based on theattenuation of photons of different energies.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention, which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable subcombination.

Although the invention has been described in conjunction with specificembodiments thereof, it is evident that many alternatives, modificationsand variations will be apparent to those skilled in the art.Accordingly, it is intended to embrace all such alternatives,modifications and variations that fall within the spirit and broad scopeof the appended claims. All publications, patents and patentapplications mentioned in this specification are herein incorporated intheir entirety by reference into the specification, to the same extentas if each individual publication, patent or patent application wasspecifically and individually indicated to be incorporated herein byreference. In addition, citation or identification of any reference inthis application shall not be construed as an admission that suchreference is available as prior art to the present invention.

1. A system for diagnosing a gastrointestinal tract, comprising: (a) aningestible device, sized to be swallowed and arranged for travelingwithin a gastrointestinal tract of a body, comprising: (i) a probe,operative to acquire, along said gastrointestinal tract, a diagnosticimage of nuclear radiation of a radiopharmaceutical; (ii) data-handlingapparatus, in signal communication with said probe, for receiving andhandling imaging data, generated by said probe; (iii) a power source,for powering said probe and data-handling apparatus; and (iv) a shell,which encapsulates said probe, data-handling apparatus, and power sourcewithin, wherein said ingestible device comprises a plurality ofnuclear-radiation detectors, arranged around said probe, and (b) firstcircuitry comprising at least one sensor adapted to determine thelocation and orientation of the ingestible device in thegastrointestinal tract; and (c) second circuitry adapted to reconstructthe diagnostic image based on said location and orientation.
 2. Thesystem of claim 1, wherein at least one of said nuclear-radiationdetectors is arranged for detecting gamma and beta radiation.
 3. Thesystem of claim 2, wherein said at least one nuclear-radiation detectoris gated substantially to a photon energy associated with a particularradioisotope.
 4. The system of claim 2, wherein said at least onenuclear-radiation detector is gated substantially to at least two photonenergies associated with two particular radioisotopes.
 5. The system ofclaim 1, wherein some of said plurality of nuclear-radiation detectorsmay be gated substantially to a photon energy associated with a specificradioisotope, while others may be gated substantially to a photon energyassociated with a different radioisotope.
 6. The system of claim 2,wherein said at least one nuclear-radiation detector is not collimated,to detect nuclear radiation impinging at any angle.
 7. The system ofclaim 1, wherein said ingestible device is arranged as a compton camera.8. A method of nuclear imaging, comprising: (1) providing a system fordiagnosing a gastrointestinal tract, comprising: (a) an ingestibledevice, sized to be swallowed and arranged for traveling within agastrointestinal tract of a body, comprising: (i) a probe, operative toacquire, along said gastrointestinal tract, a diagnostic image ofnuclear radiation of a radiopharmaceutical; (ii) data-handlingapparatus, in signal communication with said probe, for receiving andhandling imaging data, generated by said probe; (iii) a power source,for powering said probe and data-handling apparatus; and (iv) a shell,which encapsulates said probe, data-handling apparatus, and power sourcewithin, wherein said ingestible device comprises a plurality of nuclearradiation detectors, arranged around said probe, and (b) first circuitrycomprising at least one sensor adapted to determine the location andorientation of the ingestible device in the gastrointestinal tract and(c) second circuitry adapted to reconstruct the diagnostic image basedon said location and orientation; (2) scanning a radioactivity emittingsource of at least two photon energies with said ingestible device, andobtaining a count rate for the at least two photons; (3) monitoring theposition of the ingestible device using said first circuitry; and (4)calculating the depth of the radioactivity emitting source, at eachposition, based on the different attenuation of photons of differentenergies, emitted from the radioactivity emitting source.
 9. The methodof claim 8, and further including constructing an image of theradioactivity emitting source.
 10. The method of claim 8, wherein themonitoring takes place at very short time intervals of between 100 and200 milliseconds.
 11. The method of claim 8, wherein saidnuclear-radiation detector is not collimated, to detect nuclearradiation impinging at any angle.
 12. The method of claim 8, and furtherincluding image reconstruction by deconvolution algorithms.
 13. Themethod of claim 8, wherein said ingestible device comprises anuclear-radiation detector, arranged for detecting gamma and betaradiation.
 14. The method of claim 8, wherein said plurality ofnuclear-radiation detectors are arranged around the external surface ofsaid ingestible device, for detecting gamma and beta radiation.
 15. Amethod of diagnosing a gastrointestinal tract, the method comprising:(1) providing a system for diagnosing a gastrointestinal tract,comprising: (a) an ingestible device, sized to be swallowed and arrangedfor traveling within a gastrointestinal tract of a body, comprising: (i)a probe, operative to acquire, along said gastrointestinal tract, adiagnostic image of nuclear radiation of a radiopharmaceutical; (ii)data-handling apparatus, in signal communication with said probe, forreceiving and handling imaging data, generated by said probe; (iii) apower source, for powering said probe and data-handling apparatus; and(iv) a shell, which encapsulates said probe, data-handling apparatus,and power source within, wherein said ingestible device comprises aplurality of nuclear radiation detectors, arranged around said probe,and (b) first circuitry comprising at least one sensor adapted todetermine the location and orientation of the ingestible device in thegastrointestinal tract and (c) second circuitry adapted to reconstructthe diagnostic image based on said location and orientation; (2)inserting said ingestible device comprising a probe and a sensor into agastrointestinal tract of a body; (3) collecting diagnostic imaging dataalong said gastrointestinal tract by detecting nuclear radiation of aradiopharmaceutical using said plurality of nuclear radiation detectors(4) determining the location and orientation of the ingestible device inthe gastrointestinal tract by said first circuitry; and (5)reconstructing a diagnostic image from said collected imaging data basedon said location and orientation.
 16. A system according to claim 1wherein said ingestible device is shaped as a pill.
 17. A systemaccording to claim 1, wherein said ingestible device further comprises atransmitter for transmitting data to said at least one sensor, whereinthe at least one sensor determines the location and orientation of theingestible device in the gastrointestinal tract based on said data.